Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[l,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof

ABSTRACT

The present disclosure relates to processes for preparing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, solid state forms thereof, and corresponding pharmaceutical compositions, methods of treatment (including treatment of rheumatoid arthritis), kits, methods of synthesis, and products-by-process.

FIELD OF THE INVENTION

The present disclosure relates to: (a) processes for the preparation of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(referred to herein as “Compound 1”), (b) intermediates used in thepreparation of Compound 1 and processes for preparing the intermediates;(c) solid state forms of Compound 1, (d) pharmaceutical compositionscomprising one or more solid state forms of Compound 1, and, optionally,one or more additional therapeutic agents; (e) methods of treating Januskinase-associated conditions (including rheumatoid arthritis) byadministering one or more solid state forms of Compound 1 to a subjectin need thereof; (f) kits comprising a first pharmaceutical compositioncomprising a solid state form of Compound 1, and, optionally, a secondpharmaceutical composition comprising one or more additional therapeuticagents; (g) methods for the preparation of solid state forms of Compound1; and (h) solid state forms of Compound 1 prepared in accordance withsuch methods.

BACKGROUND OF THE INVENTION

(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(“Compound 1”) was first disclosed in International ApplicationWO2011/068881A1, which is herein incorporated by reference in itsentirety. The compound has activity as a Janus kinase (“JAK”) inhibitor,particularly as a JAK-1 inhibitor. Clinical trials are ongoing toevaluate the use of the compound to treat rheumatoid arthritis.

The isolation and commercial-scale preparation of a solid state form ofCompound 1 and corresponding pharmaceutical formulations havingacceptable solid state properties (including chemical stability, thermalstability, solubility, hygroscopicity, and/or particle size), compoundmanufacturability (including yield, impurity rejection duringcrystallization, filtration properties, drying properties, and millingproperties), and formulation feasibility (including stability withrespect to pressure or compression forces during tableting) present anumber of challenges that are discussed in greater detail below.Accordingly, there is a current need for one or more solid state formsof Compound 1 that have an acceptable balance of these properties andcan be used in the preparation of pharmaceutically acceptable soliddosage forms.

Additionally, currently known processes for the preparation of Compound1 involve the use of particularly hazardous reagents, such astrimethylsilyldiazomethane or diazomethane, and do not produce acrystalline product. There is thus also a need for a process forpreparing Compound 1, and pharmaceutically acceptable salts thereof,that avoids the use of particularly hazardous reagents, and can producea crystalline product and crystalline intermediates.

Additionally, sustained peak plasma concentrations can theoretically beachieved by means of sustained release matrix systems. However, whensuch systems are made of hydrophilic polymers, such as HPMC, they seldomprovide pH independent drug release of pH-dependent soluble drugs, andthey are normally incapable of attaining zero-order release except forpractically insoluble drugs. Unexpectedly, is has been discovered thatwhen tartaric acid is used as a pH-modifier in such a system, it allowsCompound 1 to be released at a steady rate regardless of the pH of theenvironment.

In an unexpected finding, it was discovered that as a tablet containingthe hydrophilic polymer matrix system erodes, Compound 1 reacts with theHPMC, creating a thicker gel layer which slows the release of Compound 1from the tablet. The resulting gel layer provided an environmentsuitable for Compound 1 to dissolve.

SUMMARY OF THE INVENTION

In one aspect, the present disclosure relates to a process for preparingCompound 1, or a pharmaceutically acceptable salt thereof. The processcomprises:

a) reacting a compound of formula (I)

or a pharmaceutically acceptable salt thereof with trimethylsulfoxoniumchloride to form a compound of formula (II)

wherein PG is a protecting group;

b) contacting the compound of formula (II) with LiX and a sulfonic acidto form a compound of formula (III)

wherein X is Br or Cl.

c) reacting the compound of formula (III) with a compound of formula(IV)

to produce a compound of formula (V)

wherein R₁ is selected from the group consisting of alkyl, aryl, and—OR₂; R₂ is alkyl; and Ts is tosyl;

d) contacting the compound of formula (V) with a perfluoro acidanhydride and an organic base to form a compound of formula (VI)

e) deprotecting the compound of formula (VI) and forming apharmaceutically acceptable salt of the compound of formula (VII):

f) reacting the pharmaceutically acceptable salt of the compound offormula (VII) with 2,2,2-trifluoroethylamine to produce Compound 1.

In another aspect, the present disclosure relates to a process forpreparing Compound 1, or a pharmaceutically acceptable salt thereof. Theprocess comprises:

a) reacting a compound of formula (Ib)

with trimethylsulfoxonium chloride in the presence ofcarbonyldiimidazole and a strong base to form a compound of formula(IIa)

wherein Cbz is carboxybenzyl;

b) contacting the compound of formula (IIa) with lithium bromide and asulfonic acid to form a compound of formula (IIIa)

c) reacting the compound of formula (IIIa) with a compound of formula(IVa)

in the presence of lithium tert-butoxide to produce a compound offormula (Va)

wherein R₂ is methyl or ethyl; and Ts is tosyl;

d) contacting the compound of formula (Va) with a perfluoro acidanhydride and an organic base to form a compound of formula (VIa)

e) deprotecting the compound of formula (VIa) to form a compound offormula (VII)

contacting the compound of formula (VII) with hydrochloric acid to forma compound of formula (VIIa)

g) reacting the compound of formula (VIIa) with2,2,2-trifluoroethylamine in the presence of carbonyldiimidazole toproduce Compound 1.

In another aspect, the present disclosure relates to a process forpreparing Compound 1. The process comprises:

a) reacting a compound of formula (I)

or a pharmaceutically acceptable salt thereof with trimethylsulfoxoniumchloride to form a compound of formula (II)

wherein PG is a protecting group;

b) contacting the compound of formula (II) with LiX and a sulfonic acidto form a compound of formula (III)

wherein X is Br or Cl.

c) reacting the compound of formula (III) with a compound of formula(IV)

to produce a compound of formula (V)

wherein R₁ is selected from the group consisting of alkyl, aryl, and—OR₂; R₂ is alkyl; and Ts is tosyl;

d) contacting the compound of formula (V) with a perfluoro acidanhydride and an organic base to produce a compound of formula (VI)

e) deprotecting the compound of formula (VI) to form a compound offormula (VII)

and contacting the compound of formula (VII) with hydrochloric acid toform the compound of formula (VIIb)

f) contacting the compound of formula (VIIb) with a base to form thecompound of formula (VII);

g) reacting the compound of formula (VII) with 2,2,2-trifluoroethylamineto produce Compound 1;

h) contacting Compound 1 with L-tartaric acid to produce a tartrate saltof Compound 1; and

i) contacting the tartrate salt with sodium carbonate and sodiumbicarbonate to produce Compound 1.

In another aspect, the present disclosure relates to a process forpreparing Compound 1, or a pharmaceutically acceptable salt thereof. Theprocess comprises:

a) converting a compound of formula (XIa):

to a compound of formula (I):

wherein PG is a protecting group;

b) reacting the compound of formula (I) with trimethylsulfoxoniumchloride to form a compound of formula (II)

c) contacting the compound of formula (II) with an anhydrous source ofHBr or HCl to form a compound of formula (III)

wherein X is Br or Cl.

d) reacting the compound of formula (III) with a compound of formula(IV)

to produce a compound of formula (V)

wherein R₁ is selected from the group consisting of alkyl, aryl, and—OR₂; R₂ is alkyl; and Ts is tosyl;

e) contacting the compound of formula (V) with a perfluoro acidanhydride and an organic base to form a compound of formula (VI)

f) deprotecting the compound of formula (VI) and forming apharmaceutically acceptable salt of the compound of formula (VII):

and

g) reacting the pharmaceutically acceptable salt of the compound offormula (VII) with 2,2,2-trifluoroethylamine to produce Compound 1.

In another aspect, the present disclosure relates to a compound offormula (II):

wherein PG is a protecting group.

In another aspect, the disclosure relates to a process for preparing acompound of formula (II):

wherein PG is a protecting group, the process comprising reacting acompound of formula (I)

or a pharmaceutically acceptable salt thereof with trimethylsulfoxoniumchloride to form the compound of formula (II).

In another aspect, the present disclosure is directed to a process forthe preparation of a compound of formula (III):

the process comprising contacting a compound of formula (II)

with LiX and a sulfonic acid to form the compound of formula (III);wherein PG is a protecting group; and X is Br or Cl.

In another aspect, the present disclosure relates to a compound offormula (Va)

wherein R₂ is methyl or ethyl; and Ts is tosyl.

In another aspect, the present disclosure relates to a process forpreparing a compound of formula (V)

the process comprising:

a) converting a compound of formula (XIa):

to a compound of formula (I)

b) reacting the compound of formula (I) with trimethylsulfoxoniumchloride to form a compound of formula (II)

c) contacting the compound of formula (II) with an anhydrous source ofHBr or HCl to form a compound of formula (III)

d) reacting the compound of formula (III) with a compound of formula(IV)

to produce the compound of formula (V);

wherein:

-   -   PG is a protecting group;    -   X is Br or Cl;    -   R₁ is selected from the group consisting of alkyl, aryl, and        —OR₂;    -   R₂ is alkyl; and    -   Ts is tosyl.

In another aspect, the disclosure is directed to a process for preparinga crystalline compound of formula (V)

the process comprising:

a) reacting a compound of formula (III)

with a compound of formula (IV):

to produce the compound of formula (V);

wherein:

-   -   PG is a protecting group;    -   X is Br or Cl    -   R₁ is —OR₂;    -   R₂ is methyl or ethyl; and    -   Ts is tosyl.

In another aspect, the present disclosure relates to a compound offormula (IVa):

wherein R₂ is methyl or ethyl, and Ts is tosyl.

In another aspect, the present disclosure relates to a process forpreparing a compound of formula (IVa):

wherein R₂ is methyl or ethyl, and Ts is tosyl, the process comprising:

a) reacting a compound of formula (XVII)

-   -   with trimethylsilylacetylene in the presence of a catalyst to        form a compound of formula (XVIII):

wherein TMS is trimethylsilyl;

b) contacting the compound of formula (XVIII) with p-toluenesulfonylchloride in the presence of a base to form a compound of formula (XIX)

wherein Ts is tosyl; and

c) reacting the compound of formula (XIX) with a carbamate in thepresence of a catalyst and a ligand to form the compound of formula(IVa), wherein the carbamate is selected from the group consisting ofmethyl carbamate and ethyl carbamate.

In another aspect, the present disclosure relates to a compound offormula (VII):

or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure relates to a process forpreparing a compound of formula (Ib)

wherein Cbz is carboxybenzyl, the process comprising:

(i) reacting carboxybenzyl-glycine ethyl ester with ethyl acrylate toform a compound of formula (VIII):

(ii) protecting the compound of formula (VIII) to form a compound offormula (IX):

wherein R³ is selected from the group consisting of CF₃SO₂—; CH₃SO₂—;and tosyl;

(iii) contacting the compound of formula (IX) with one of ethyl boronicacid, ethyl magnesium bromide, or ethyl zinc chloride in the presence ofa catalyst to form a compound of formula (X):

(iv) hydrolyzing the compound of formula (X) to produce the compound offormula (XI):

(v) converting the compound of formula (XI) to the compound of formula(XII):

(vi) contacting the compound of formula (XII) with dicyclohexylamine toform the compound of formula (Ib).

In another aspect, the present disclosure relates to thedicyclohexylamine salt of(3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate.

In one aspect, the present disclosure relates to pharmaceuticallyacceptable solid state forms of Compound 1.

In another aspect, the present disclosure relates to Amorphous Freebaseof Compound 1.

In another aspect, the present disclosure relates to crystallineCompound 1.

In another aspect, the present disclosure relates to crystallinehydrates of Compound 1.

In another aspect, the present disclosure relates to crystallinetartrates of Compound 1.

In another aspect, the present disclosure relates to the FreebaseHydrate Form C of Compound 1.

In another aspect, the present disclosure relates to the FreebaseHydrate Form B of Compound 1.

In another aspect, the present disclosure relates to crystallineanhydrates of Compound 1.

In another aspect, the present disclosure relates to the FreebaseAnhydrate Form D of Compound 1.

In another aspect, the present disclosure relates to pharmaceuticalcompositions comprising one or more solid state forms of Compound 1, anda pharmaceutically acceptable carrier.

In another aspect, the present disclosure is directed to apharmaceutical composition comprising one or more solid state forms ofCompound 1, from about 10 w/w % to about 35 w/w % of an organic acidselected from the group consisting of tartaric acid, fumaric acid,citric acid, succinic acid, malic acid, and combinations thereof, and apharmaceutically acceptable carrier. In one embodiment, the solid stateform is Tartrate Hydrate. In one embodiment, the solid state form isFreebase Hydrate Form C.

In another aspect, the present disclosure relates to pharmaceuticalcompositions comprising one or more solid state forms of Compound 1,and, optionally, one or more additional therapeutic agents.

In another aspect, the present disclosure relates to methods of treatinga JAK-associated condition (such as rheumatoid arthritis) in a humansubject suffering from or susceptible to such a condition comprisingadministering to the subject a therapeutically effective amount of asolid state form of Compound 1. In another aspect, the disclosurerelates to a pharmaceutical composition comprising a therapeuticallyeffective amount of a solid state form of Compound 1 as described in thepresent disclosure, for use in treatment of a JAK-associated condition(such as rheumatoid arthritis) in a subject, particularly in a humansubject suffering from or susceptible to the condition.

In another aspect, the present disclosure relates to methods of treatingrheumatoid arthritis, wherein the term “rheumatoid arthritis” includesjuvenile rheumatoid arthritis, juvenile idiopathic arthritis, ankylosingspondylitis disease, Sjogren's syndrome, psoriatic arthritis.

In another aspect, the present disclosure relates to methods of treatinginflammatory bowel disease, wherein the term “inflammatory boweldisease” includes Crohn's disease, pediatric Crohn's disease andulcerative colitis.

In another aspect, the present disclosure relates to a method oftreating a condition selected from the group consisting of rheumatoidarthritis, juvenile idiopathic arthritis, Crohn's disease, ulcerativecolitis, psoriasis, plaque psoriasis, nail psoriasis, psoriaticarthritis, ankylosing spondylitis, alopecia areata, hidradenitissuppurativa, atopic dermatitis and systemic lupus erythematosus in ahuman subject suffering from or susceptible to such a condition, themethod comprising administering to the subject a therapeuticallyeffective amount a solid state form of Compound 1. In another aspect,the disclosure relates to a pharmaceutical composition comprising atherapeutically effective amount of a solid state form of Compound 1 asdescribed in the present disclosure, for use in treatment of a conditionselected from the group consisting of rheumatoid arthritis, juvenileidiopathic arthritis, Crohn's disease, ulcerative colitis, psoriasis,plaque psoriasis, nail psoriasis, psoriatic arthritis, ankylosingspondylitis, alopecia areata, hidradenitis suppurativa, atopicdermatitis, and systemic lupus erythematosus in a subject, particularlyin a human subject suffering from or susceptible to the condition.

In another aspect, the present disclosure relates to methods of treatinga JAK-associated condition (such as rheumatoid arthritis) in a humansubject suffering from or susceptible to such a condition comprisingadministering to the subject a solid state form of Compound 1, incombination with one or more additional therapeutic agents (e.g., atherapeutic agent for treating rheumatoid arthritis that is not a JAKinhibitor). In another aspect, the disclosure relates to apharmaceutical composition comprising a solid state form of Compound 1,as described in the present disclosure, in combination with one or moreadditional therapeutic agents (e.g., a therapeutic agent for treatingrheumatoid arthritis that is not a JAK inhibitor), for use in treatmentof a JAK-associated condition (such as rheumatoid arthritis) in asubject, particularly in a human subject suffering from or susceptibleto the condition.

In another aspect, the present disclosure relates to a method oftreating moderate to severely active rheumatoid arthritis, the methodcomprising administering a therapeutically effective amount of Compound1 in one or more forms as disclosed herein to a subject suffering fromor susceptible to the condition. In a particular aspect, such a methodmay comprise administering 7.5 mg once daily or 15 mg once daily, or 30mg once daily, or 45 mg once daily of the Compound 1, in one or moreforms as disclosed herein, to the subject. In this or another particularaspect, the subject may be administered the Compound 1 in Freebase FormC. In this or yet another particular aspect, the subject may have aninadequate response to methotrexate. In this or yet another particularaspect, the subject may have an inadequate response to biologicsmedicines approved for rheumatoid arthritis. In this or yet anotherparticular aspect, the subject may have not previously been administeredbiologics medicines approved for rheumatoid arthritis.

In another aspect, the present disclosure relates to a method oftreating an adult subject having moderate to severely active rheumatoidarthritis, the method comprising administering to the subject: a) about7.5 mg of Compound 1 freebase, or a pharmaceutically acceptable saltthereof, or a crystalline hydrate or a crystalline anhydrate of Compound1 in an amount sufficient to deliver to the subject about 7.5 mg ofCompound 1 freebase equivalent; or b) about 15 mg of Compound 1freebase, or a pharmaceutically acceptable salt thereof, or acrystalline hydrate or a crystalline anhydrate of Compound 1 in anamount sufficient to deliver to the subject about 15 mg of Compound 1freebase equivalent; or c) about 30 mg of Compound 1 freebase, or apharmaceutically acceptable salt thereof, or a crystalline hydrate or acrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 30 mg of Compound 1 freebase equivalent; or d)about 45 mg of Compound 1 freebase, or a pharmaceutically acceptablesalt thereof, or a crystalline hydrate or a crystalline anhydrate ofCompound 1 in an amount sufficient to deliver to the subject about 45 mgof Compound 1 freebase equivalent. In one embodiment, the presentdisclosure is directed to a pharmaceutical composition for use intreating an adult subject having moderate to severely active rheumatoidarthritis, the use comprising administering the pharmaceuticalcomposition to the subject, wherein the pharmaceutical compositioncomprises a) about 7.5 mg of Compound 1 freebase, or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or a crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 7.5 mg of Compound 1 freebase equivalent; or b) about 15mg of Compound 1 freebase, or a pharmaceutically acceptable saltthereof, or a crystalline hydrate or a crystalline anhydrate of Compound1 in an amount sufficient to deliver to the subject about 15 mg ofCompound 1 freebase equivalent; or c) about 30 mg of Compound 1freebase, or a pharmaceutically acceptable salt thereof, or acrystalline hydrate or a crystalline anhydrate of Compound 1 in anamount sufficient to deliver to the subject about 30 mg of Compound 1freebase equivalent; or d) about 45 mg of Compound 1 freebase, or apharmaceutically acceptable salt thereof, or a crystalline hydrate or acrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 45 mg of Compound 1 freebase equivalent.

In another embodiment, the present disclosure relates to a method oftreating structural damage associated with rheumatoid arthritis in anadult subject, the method comprising administering to the subject: a)about 7.5 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 7.5 mg per day of Compound 1 freebase equivalent; or b)about 15 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 15 mg per day of Compound 1 freebase equivalent; or c)about 30 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg per day of Compound 1 freebase equivalent; or d)about 45 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 45 mg per day of Compound 1 freebase equivalent; such thatthe structural damage in the adult subject is inhibited or lessened. Inone embodiment, the disclosure relates to a pharmaceutical compositionfor use in treating structural damage associated with rheumatoidarthritis in an adult subject, the use comprising administering thepharmaceutical composition to the subject, wherein the pharmaceuticalcomposition comprises: a) about 7.5 mg per day of Compound 1 freebase ora pharmaceutically acceptable salt thereof, or a crystalline hydrate orcrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 7.5 mg per day of Compound 1 freebase equivalent;or b) about 15 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 15 mg per day of Compound 1 freebase equivalent; or c)about 30 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg per day of Compound 1 freebase equivalent; or d)about 45 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 45 mg per day of Compound 1 freebase equivalent; such thatthe structural damage in the adult subject is inhibited or lessened.

In another aspect, the disclosure is directed to a method of treatingmoderate to severely active rheumatoid arthritis in an adult subject,the method comprising administering to the subject: a) about 7.5 mg perday of Compound 1 freebase or a pharmaceutically acceptable saltthereof, or a crystalline hydrate or crystalline anhydrate of Compound 1in an amount sufficient to deliver to the subject about 7.5 mg per dayof Compound 1 freebase equivalent; or b) about 15 mg per day of Compound1 freebase or a pharmaceutically acceptable salt thereof, or acrystalline hydrate or crystalline anhydrate of Compound 1 in an amountsufficient to deliver to the subject about 15 mg per day of Compound 1freebase equivalent; or c) about 30 mg per day of Compound 1 freebase ora pharmaceutically acceptable salt thereof, or a crystalline hydrate orcrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 30 mg per day of Compound 1 freebase equivalent; ord) about 45 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 45 mg per day of Compound 1 freebase equivalent; whereinthe subject has symptoms selected from the group consisting of at least6 swollen joints, at least 6 tender joints, and combinations thereofprior to treating. In one embodiment, the disclosure is directed to apharmaceutical composition for use in treating moderate to severelyactive rheumatoid arthritis in an adult subject, the use comprisingadministering the pharmaceutical composition to the subject, wherein thepharmaceutical composition comprises: a) about 7.5 mg per day ofCompound 1 freebase or a pharmaceutically acceptable salt thereof, or acrystalline hydrate or crystalline anhydrate of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg per day of Compound 1freebase equivalent; or b) about 15 mg per day of Compound 1 freebase ora pharmaceutically acceptable salt thereof, or a crystalline hydrate orcrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 15 mg per day of Compound 1 freebase equivalent; orc) about 30 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg per day of Compound 1 freebase equivalent; or d)about 45 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 45 mg per day of Compound 1 freebase equivalent; whereinthe subject has symptoms selected from the group consisting of at least6 swollen joints, at least 6 tender joints, and combinations thereofprior to treating.

In another aspect, the disclosure is directed to a method of reducingsigns and symptoms of rheumatoid arthritis in an adult subject withmoderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject: a) about 7.5 mg per day ofCompound 1 freebase or a pharmaceutically acceptable salt thereof, or acrystalline hydrate or crystalline anhydrate of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg of Compound 1 freebaseequivalent; or b) about 15 mg per day of Compound 1 freebase or apharmaceutically acceptable salt thereof, or a crystalline hydrate orcrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 15 mg of Compound 1 freebase equivalent; or c)about 30 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg of Compound 1 freebase equivalent; or d) about 45 mgper day of Compound 1 freebase or a pharmaceutically acceptable saltthereof, or a crystalline hydrate or crystalline anhydrate of Compound 1in an amount sufficient to deliver to the subject about 45 mg ofCompound 1 freebase equivalent. In one embodiment, the disclosure isdirected to a pharmaceutical composition for use in reducing signs andsymptoms of rheumatoid arthritis in an adult subject with moderately toseverely active rheumatoid arthritis, the use comprising administeringthe pharmaceutical composition to the subject, wherein thepharmaceutical composition comprises: a) about 7.5 mg per day ofCompound 1 freebase or a pharmaceutically acceptable salt thereof, or acrystalline hydrate or crystalline anhydrate of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg of Compound 1 freebaseequivalent; or b) about 15 mg per day of Compound 1 freebase or apharmaceutically acceptable salt thereof, or a crystalline hydrate orcrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 15 mg of Compound 1 freebase equivalent; or c)about 30 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg of Compound 1 freebase equivalent; or d) about 45 mgper day of Compound 1 freebase or a pharmaceutically acceptable saltthereof, or a crystalline hydrate or crystalline anhydrate of Compound 1in an amount sufficient to deliver to the subject about 45 mg ofCompound 1 freebase equivalent.

In another aspect, the present disclosure relates to kits comprising oneor more pharmaceutical compositions comprising a solid state form ofCompound 1. The kit optionally can comprise another pharmaceuticalcomposition comprising one or more additional therapeutic agents and/orinstructions, for example, instructions for using the kit.

In another aspect, the present disclosure relates to methods for thepreparation of a solid state form of Compound 1.

In another aspect, the present disclosure relates to solid state formsof Compound 1 prepared in accordance with such methods.

In another aspect, the present disclosure relates to a method oftreating an adult subject having moderate to severely active rheumatoidarthritis, the method comprising administering to the subject about 7.5mg, or about 15 mg, or about 30 mg, or about 45 mg of Compound 1freebase, or a crystalline hydrate of Compound 1 in an amount sufficientto deliver to the subject about 7.5 mg, or about 15 mg, or about 30 mg,or about 45 mg of Compound 1 freebase equivalent. In this or anotherparticular aspect, the hydrate may be a hemihydrate. In this or anotheraspect, the hemihydrate may be Freebase Hydrate Form C. In this or yetanother particular aspect, the subject may have an inadequate responseor tolerance to one or more disease-modifying antirheumatic drugs(DMARDS), such as methotrexate. In this or yet another particularaspect, the subject may have not previously been administered DMARDS. Inthis or yet another particular aspect, the subject may further beadministered one or more DMARD.

In another aspect, the present disclosure relates to a method oftreating structural damage associated with rheumatoid arthritis in anadult subject, the method comprising administering to the subject about7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day ofCompound 1 freebase or a crystalline hydrate of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg, or about 15 mg, orabout 30 mg, or about 45 mg per day of Compound 1 freebase equivalent,such that the structural damage in the adult subject is inhibited orlessened. In this or another particular aspect, the hydrate may be ahemihydrate. In this or another aspect, the hemihydrate may be FreebaseHydrate Form C.

In another aspect, the present disclosure relates to a method oftreating moderate to severely active rheumatoid arthritis in an adultsubject, the method comprising administering to the subject about 7.5mg, or about 15 mg, or about 30 mg, or about 45 mg per day of Compound 1freebase or a crystalline hydrate of Compound 1 in an amount sufficientto deliver to the subject about 7.5 mg, or about 15 mg, or about 30 mg,or about 45 mg per day of Compound 1 freebase equivalent, wherein thesubject has symptoms selected from the group consisting of at least 6swollen joints, at least 6 tender joints, and combinations thereof priorto treating. In this or another particular aspect, the hydrate may be ahemihydrate. In this or another aspect, the hemihydrate may be FreebaseHydrate Form C.

In another aspect, the present disclosure relates to a method ofreducing signs and symptoms of rheumatoid arthritis in an adult subjectwith moderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 7.5 mg per day of Compound1 freebase or a crystalline hydrate of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg of Compound 1 freebaseequivalent. In this or another particular aspect, the hydrate may be ahemihydrate. In this or another aspect, the hemihydrate may be FreebaseHydrate Form C.

In another aspect, the present disclosure relates to a method ofreducing signs and symptoms of rheumatoid arthritis in an adult subjectwith moderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 15 mg per day of Compound1 freebase or a crystalline hydrate of Compound 1 in an amountsufficient to deliver to the subject about 15 mg of Compound 1 freebaseequivalent. In this or another particular aspect, the hydrate may be ahemihydrate. In this or another aspect, the hemihydrate may be FreebaseHydrate Form C.

In another aspect, the present disclosure relates to a method ofreducing signs and symptoms of rheumatoid arthritis in an adult subjectwith moderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 30 mg per day of Compound1 freebase or a crystalline hydrate of Compound 1 in an amountsufficient to deliver to the subject about 30 mg of Compound 1 freebaseequivalent. In this or another particular aspect, the hydrate may be ahemihydrate. In this or another aspect, the hemihydrate may be FreebaseHydrate Form C.

In another aspect, the present disclosure relates to a method ofreducing signs and symptoms of rheumatoid arthritis in an adult subjectwith moderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 45 mg per day of Compound1 freebase or a crystalline hydrate of Compound 1 in an amountsufficient to deliver to the subject about 45 mg of Compound 1 freebaseequivalent. In this or another particular aspect, the hydrate may be ahemihydrate. In this or another aspect, the hemihydrate may be FreebaseHydrate Form C.

In another aspect, the present disclosure relates to a pharmaceuticalcomposition comprising a crystalline hydrate of Compound 1 and apharmaceutically acceptable carrier, wherein the composition comprisesthe crystalline hydrate in an amount sufficient to deliver about 7.5 mgof Compound 1 freebase equivalent. In this or another particular aspect,the hydrate may be a hemihydrate. In this or another aspect, thehemihydrate may be Freebase Hydrate Form C.

In another aspect, the present disclosure relates to a pharmaceuticalcomposition comprising a crystalline hydrate of Compound 1 and apharmaceutically acceptable carrier, wherein the composition comprisesthe crystalline hydrate in an amount sufficient to deliver about 15 mgof Compound 1 freebase equivalent. In this or another particular aspect,the hydrate may be a hemihydrate. In this or another aspect, thehemihydrate may be Freebase Hydrate Form C.

In another aspect, the present disclosure relates to a pharmaceuticalcomposition comprising a crystalline hydrate of Compound 1 and apharmaceutically acceptable carrier, wherein the composition comprisesthe crystalline hydrate in an amount sufficient to deliver about 30 mgof Compound 1 freebase equivalent. In this or another particular aspect,the hydrate may be a hemihydrate. In this or another aspect, thehemihydrate may be Freebase Hydrate Form C.

In another aspect, the present disclosure relates to a pharmaceuticalcomposition comprising a crystalline hydrate of Compound 1 and apharmaceutically acceptable carrier, wherein the composition comprisesthe crystalline hydrate in an amount sufficient to deliver about 45 mgof Compound 1 freebase equivalent. In this or another particular aspect,the hydrate may be a hemihydrate. In this or another aspect, thehemihydrate may be Freebase Hydrate Form C.

In another aspect, the present disclosure relates to a method oftreating an adult subject having moderate to severely active rheumatoidarthritis, the method comprising administering to the subject about 7.5mg, or about 15 mg, or about 30 mg, or about 45 mg of a crystallinehydrate of Compound 1. In this or another particular aspect, the hydratemay be a hemihydrate. In this or another aspect, the hemihydrate may beFreebase Hydrate Form C.

In another aspect, the present disclosure relates to a method oftreating structural damage associated with rheumatoid arthritis in anadult subject, the method comprising administering to the subject about7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day of acrystalline hydrate of Compound 1, such that the structural damage inthe adult subject is inhibited or lessened. In this or anotherparticular aspect, the hydrate may be a hemihydrate. In this or anotheraspect, the hemihydrate may be Freebase Hydrate Form C.

In another aspect, the present disclosure relates to a method oftreating moderate to severely active rheumatoid arthritis in an adultsubject, the method comprising administering to the subject about 7.5mg, or about 15 mg, or about 30 mg, or about 45 mg per day of acrystalline hydrate of Compound 1, wherein the subject has symptomsselected from the group consisting of at least 6 swollen joints, atleast 6 tender joints, and combinations thereof prior to treating. Inthis or another particular aspect, the hydrate may be a hemihydrate. Inthis or another aspect, the hemihydrate may be Freebase Hydrate Form C.

In another aspect, the present disclosure relates to a method ofreducing signs and symptoms of rheumatoid arthritis in an adult subjectwith moderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 7.5 mg, or about 15 mg, orabout 30 mg, or about 45 mg per day of a crystalline hydrate ofCompound 1. In this or another particular aspect, the hydrate may be ahemihydrate. In this or another aspect, the hemihydrate may be FreebaseHydrate Form C.

In another aspect, the present disclosure is directed to an extendedrelease formulation for oral administration comprising Compound 1 or apharmaceutically acceptable salt thereof, a hydrophilic polymer, and apH modifier, wherein the hydrophilic polymer, in contact with water,forms a gel layer that provides an environment suitable for Compound 1and the pH modifier to dissolve.

In another aspect, the present disclosure is directed to a process forpreparing a pharmaceutical composition, the process comprising: (a)combining Compound 1 or a pharmaceutically acceptable salt thereof, or asolid state form of Compound 1, and at least a portion of one additionalcomposition component to form a dry granulation mixture; (b) contactingthe dry granulation mixture with a granulation fluid to form a wetgranulation mixture; (c) drying the wet granulation mixture to form agranulated material; (d) milling the granulated material to form amilled granulated material; (e) combining the milled granulationmaterial with any remaining composition components; and (f) compressingthe composition to form the pharmaceutical composition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A schematically illustrates one method of preparing the AmorphousFreebase.

FIG. 1B schematically illustrates one method of preparing the FreebaseHydrate Form C.

FIG. 1C schematically illustrates one method of preparing the TartrateHydrate.

FIGS. 2A and 2B are powder X-ray diffraction patterns corresponding tothe Amorphous Freebase (via precipitation) and the Amorphous Freebase(via dehydration), respectively.

FIG. 3A is a powder X-ray diffraction pattern corresponding to theFreebase Solvate Form A (Isopropyl Acetate/Water Solvate).

FIG. 3B is a powder X-ray diffraction pattern corresponding to theFreebase Hydrate Form B.

FIG. 3C is a powder X-ray diffraction pattern corresponding to theFreebase Hydrate Form C.

FIG. 3D is a powder X-ray diffraction pattern corresponding to theTartrate Hydrate. The experimental PXRD pattern is shown at the bottomof FIG. 3D and the calculated PXRD pattern is shown at the top of FIG.3D.

FIG. 3E is a powder X-ray diffraction pattern corresponding to theHydrochloride Solvate Form AA.

FIG. 3F is powder X-ray diffraction pattern corresponding to theHydrochloride Solvate Form BB.

FIG. 3G is a powder X-ray diffraction pattern corresponding to theHydrochloride Solvate Form CC.

FIG. 3H is a powder X-ray diffraction pattern corresponding to L-MaleateForm AAA.

FIG. 3I is a powder X-ray diffraction pattern corresponding to L-MaleateForm BBB.

FIG. 3J is a powder X-ray diffraction pattern corresponding to FreebaseAnhydrate Form D.

FIGS. 4A and 4B are thermogravimetric analysis thermograms correspondingto the Amorphous Freebase (via precipitation) and the Amorphous Freebase(via dehydration), respectively.

FIG. 4C is a thermogravimetric analysis thermogram corresponding to theFreebase Solvate Form A.

FIG. 4D is a thermogravimetric analysis thermogram corresponding to theFreebase Hydrate Form B.

FIG. 4E is a thermogravimetric analysis thermogram corresponding to theFreebase Hydrate Form C.

FIG. 4F is a thermogravimetric analysis thermogram corresponding to theTartrate Hydrate.

FIG. 4G is a thermogravimetric analysis thermogram corresponding to theHydrochloride Solvate Form AA.

FIG. 4H is a thermogravimetric analysis thermogram corresponding toL-Maleate Form BBB.

FIG. 4I is a thermogravimetric analysis thermogram corresponding toFreebase Anhydrate Form D.

FIG. 5A is a differential scanning calorimetry thermogram correspondingto the Amorphous Freebase (via dehydration).

FIG. 5B is a differential scanning calorimetry thermogram correspondingto the Freebase Hydrate Form B.

FIG. 5C is a differential scanning calorimetry thermogram correspondingto the Freebase Hydrate Form C.

FIG. 5D is a differential scanning calorimetry thermogram correspondingto the Tartrate Hydrate.

FIG. 5E is a differential scanning calorimetry thermogram correspondingto the Freebase Anhydrate Form D.

FIG. 6A is a moisture sorption isotherm corresponding to the AmorphousFreebase (via dehydration).

FIG. 6B is a moisture sorption isotherm corresponding to the FreebaseHydrate Form C.

FIG. 6C is a moisture sorption isotherm corresponding to the TartrateHydrate.

FIG. 6D is a moisture sorption isotherm corresponding to the FreebaseAnhydrate Form D.

FIG. 7 is a comparison of the dissolution profile of the extendedrelease tablets from Example 26 (Freebase Hydrate Form C) and Example 27(Amorphous Freebase) at pH 6.8.

FIG. 8 is a comparison of the dissolution profile of the extendedrelease tablets from Example 24 (ER1), Example 25 (ER2), and Example 26(ER3) in a dual pH system and at pH 6.8.

FIG. 9 is a comparison of the dissolution profile of the extendedrelease tablet from Example 32 (ER4) and Example 33 (ER4, no mannitol)at pH 1.2, pH 6.8, or a dual pH system.

FIG. 10 is a comparison of the dissolution profile of the extendedrelease tablet from Example 34 (ER5) at pH 1.2, pH 6.8, and a dual pHsystem.

FIG. 11 is a comparison of the dissolution profile of the extendedrelease tablet from Example 35 (ER6) at pH 1.2, pH 6.8, and a dual pHsystem.

FIG. 12 is a comparison of the dissolution profile of the extendedrelease tablet from Example 28 (ER7) and Example 32 (ER4) in a dual pHsystem.

FIG. 13 is a comparison of the dissolution profile of the extendedrelease tablet from Example 31 (ER8) and Example 32 (ER4) in a dual pHsystem.

FIG. 14 is comparison of the dissolution profile of the extended releasetablets from Example 24 (ER1), Example 26 (ER3), and Example 32 (ER4) ina dual pH system.

FIGS. 15A-15H are comparisons of the dissolution profile at pH 1.2 and6.8 for the extended release tablets from Example 43, which containeither HPMC (FIGS. 15A-15D) or Carbopol® (FIGS. 15E-15H) as releasecontrol polymers, and tartaric acid (FIGS. 15A and 15E), citric acid(FIGS. 15B and 15F), succinic acid (FIGS. 15C and 15G), or fumaric acid(FIGS. 15D and 15H) as a pH modifier.

FIGS. 16A and 16B show the Compound 1 mean plasma concentration versustime following administration of a 12 mg immediate release capsule(Regimen A) or a 15 mg once-daily extended release tablet (Regimen B)under fasting conditions using a linear (FIG. 16A) or semi-log (FIG.16B) scale.

FIGS. 17A and 17B show the Compound 1 mean plasma concentration versustime following administration of a 24 mg dose (2×12 mg) of immediaterelease capsule (Regimen C) or a 30 mg once-daily extended releasetablet (Regimen D) under fasting conditions using a linear (FIG. 17A) orsemi-log (FIG. 17B) scale.

FIGS. 18A and 18B show the Compound 1 mean plasma concentration versustime following administration of a 30 mg once-daily extended releasetablet under fasting conditions (Regimen D) or a 30 mg once-dailyextended release tablet after consumption of a high-fat meal (Regimen E)using a linear (FIG. 18A) or semi-log (FIG. 18B) scale.

FIG. 19 shows the Compound 1 mean plasma concentration versus timefollowing administration of a 15 mg once-daily extended release tablet(Regimen F) or a 30 mg once-daily extended release tablet (Regimen G)for seven days under non-fasting conditions.

FIG. 20 shows the Compound 1 mean plasma concentration versus timefollowing administration of 6 mg twice daily immediate release capsules(Regimen K) or a 15 mg once-daily extended release tablet (Regimen L)for seven days under fasting conditions.

FIG. 21 shows the Compound 1 pre-morning dose trough concentration(C_(trough)) following administration of 6 mg twice daily immediaterelease capsules or a 15 mg once-daily extended release tablet overseven days under fasting conditions.

FIG. 22 shows the Compound 1 mean plasma concentration versus timefollowing administration of 12 mg twice daily immediate release capsules(Regimen M) or a 30 mg once-daily extended release tablet (Regimen N)for seven days under fasting conditions.

FIG. 23 shows the Compound 1 pre-morning dose trough concentration(C_(trough)) following administration of 12 mg twice daily immediaterelease capsules or a 30 mg once-daily extended release tablet overseven days under fasting conditions.

FIGS. 24A and 24B show the Compound 1 mean plasma concentration versustime following administration under fasting conditions of various 30 mgonce-daily extended release tablets having varying concentrations oftartaric acid, using a linear (FIG. 24A) or log-linear (FIG. 24B) scale.

FIGS. 25A and 25B show the Compound 1 mean plasma concentration versustime following administration under fasting conditions or after ahigh-fat meal (non-fasting) of a 30 mg once-daily extended releasetablet (ER10) using a linear (FIG. 25A) or log-linear (FIG. 25B) scale.

FIGS. 26A and 26B show the individual change in Compound 1 C_(max) (FIG.26A) and AUC_(inf) (FIG. 26B) following administration under fastingconditions or after a high-fat meal (non-fasting) of a 30 mg once-dailyextended release tablet (ER10).

FIGS. 27A and 27B show the Compound 1 mean plasma concentration versustime following administration under fasting conditions or after ahigh-fat meal (non-fasting) of a 30 mg once-daily extended releasetablet (ER11) using a linear (FIG. 27A) or log-linear (FIG. 27B) scale.

FIGS. 28A and 28B show the individual change in Compound 1 C_(max) (FIG.28A) and AUC_(inf) (FIG. 28B) following administration under fastingconditions or after a high-fat meal (non-fasting) of a 30 mg once-dailyextended release tablet (ER11).

FIGS. 29A and 29B show the Compound 1 mean plasma concentration versustime following administration under fasting conditions or after ahigh-fat meal (non-fasting) of a 30 mg once-daily extended releasetablet (ER12) using a linear (FIG. 29A) or log-linear (FIG. 29B) scale.

FIGS. 30A and 30B show the individual change in Compound 1 C_(max) (FIG.30A) and AUC_(inf) (FIG. 30B) following administration under fastingconditions or after a high-fat meal (non-fasting) of a 30 mg once-dailyextended release tablet (ER12).

FIG. 31 shows a plot of the pH of the gel formed on tablets comprisingvarying amounts of tartaric acid.

FIGS. 32A and 32B show the Compound 1 mean plasma concentrations versustime profiles following administration of single oral doses of Compound1 immediate release capsules to healthy subjects using a linear (FIG.32A) or log-linear (FIG. 32B) scales.

FIG. 33 shows the Compound 1 mean plasma concentration versus timeprofiles following administration of multiple twice-daily oral doses ofCompound 1 immediate release capsules to healthy subjects.

FIG. 34A-34D shows the dose-normalized Compound 1 mean C_(max) and AUCafter administration of single doses in healthy subjects (FIG.34A—single dose, C_(max); FIG. 34C—single dose, AUC_(∞)) andmultiple-doses in healthy subjects and subjects with rheumatoidarthritis (FIG. 34B—multiple-doses, C_(max); FIG. 34D—multiple-doses,AUC₀₋₁₂).

FIGS. 35A and 35B show the lack of effect of concomitant methotrexateadministration on Compound 1 dose-normalized AUC (FIG. 35A) and lack ofeffect of concomitant Compound 1 administration on methotrexatedose-normalized AUC (FIG. 35B).

FIG. 36A shows the ACR20, ACR50, and ACR70 response rate at week 12following administration of placebo or various doses of Compound 1 tosubjects with active rheumatoid arthritis and prior inadequate responseor intolerance to an anti-TNF biologic agent (*P<0.05; **P<0.01;***P<0.001 relative to placebo; modified intent-to-treat population(NRI)). FIG. 36B shows the ACR20 response rate at week 12 in the samepopulation, broken down by number of prior anti-TNF biologic agents.

FIGS. 37A-37D show the ACR20 (FIG. 37A), ACR50 (FIG. 37B), and ACR70(FIG. 37C) responses or DAS28(CRP) mean change from baseline (FIG. 37D)over time following administration of placebo or various doses ofCompound 1 to subjects with active rheumatoid arthritis and priorinadequate response or intolerance to an anti-TNF biologic agent(*P<0.05; **P<0.01; ***P<0.001 relative to placebo; modifiedintent-to-treat population (NRI)). FIG. 37E shows the subjects achievinga DAS28(CRP) score of ≤3.2 or <2.6 at week 12 in the same population.FIG. 37F shows the subjects achieving low disease activity (LDA) orclinical remission (CR) based on clinical disease activity index (CDAI)criteria (LDA is CDAI≤10; CR is CDAI≤2.8) at week 12 in the samepopulation.

FIG. 38A shows the mean hemoglobin levels over time for all subjectsfollowing administration of placebo or various doses of Compound 1 tosubjects with active rheumatoid arthritis and prior inadequate responseor intolerance to an anti-TNF biologic agent (safety population withobserved data (no imputation of missing values)). FIG. 38B shows themean hemoglobin change from baseline over time in subjects withhigh-sensitivity C-reactive protein (hsCRP) greater than the upper limitof normal (ULN) (normal ranges for hemoglobin: 11.5-15.5 g/dL in femalesand 13.2-17.0 g/dL in males; ULN for hsCRP=5 mg/L).

FIG. 39 shows the subject disposition for the study described in Example55.

FIGS. 40A and 40B show the subject disposition for the study describedin Example 56.

FIG. 41 shows the ACR20, ACR50, and ACR70 responses at week 12 followingadministration of placebo or various doses of Compound 1 to subjectswith active rheumatoid arthritis and inadequate response to methotrexate(*P<0.05; **P<0.01; ***P<0.001 relative to placebo; modifiedintent-to-treat population with NRI of missing values).

FIGS. 42A-42D show the ACR20 (FIG. 42A, NRI analysis), ACR50 (FIG. 42B,NRI analysis), and ACR70 (FIG. 42C, NRI analysis) responses orDAS28(CRP) mean change from baseline (FIG. 42D, observed cases) overtime following administration of placebo or various doses of Compound 1to subjects with active rheumatoid arthritis and inadequate response tomethotrexate (*P<0.05; **P<0.01; ***P<0.001 relative to placebo;modified intent-to-treat population).

FIGS. 43A and 43B show subjects achieving a DAS28(CRP) score of ≤3.2 or<2.6 (FIG. 44A) or CDAI of ≤10 or ≤2.8) at week 12 followingadministration of placebo or various doses of Compound 1 to subjectswith active rheumatoid arthritis and inadequate response to methotrexate(*P<0.05; **P<0.01; ***P<0.001 relative to placebo; modifiedintent-to-treat population (NRI)). For FIGS. 43A and 43B, the bottomnumber indicates the percentage of subjects who achieved both cutoffvalues, the middle number indicates the percentage of subjects whoachieved the less stringent cutoff but not the more stringent cutoffvalue, and the top number indicates the percentage of patients whoachieved either cutoff value.

FIGS. 44A-44C show the mean change in hemoglobin from baseline over timeby treatment group in all subjects (FIG. 44A), subjects with hsCRP≤5mg/mL at baseline (FIG. 44B), and subjects with hsCRP>5 mg/mL atbaseline (FIG. 44C) following administration of placebo or various dosesof Compound 1 to subjects with active rheumatoid arthritis andinadequate response to methotrexate (safety population with observeddata (no imputation of missing values)).

DETAILED DESCRIPTION OF THE INVENTION

This written description uses examples to disclose the invention andalso to enable any person skilled in the art to practice the invention,including making and using any of the disclosed solid state forms orcompositions, and performing any of the disclosed methods or processes.The patentable scope of the invention is defined by the claims, and mayinclude other examples that occur to those skilled in the art. Suchother examples are intended to be within the scope of the claims if theyhave elements that do not differ from the literal language of theclaims, or if they include equivalent elements.

I. DEFINITIONS

Section headings as used in this section and the entire disclosure arenot intended to be limiting.

Where a numeric range is recited, each intervening number within therange is explicitly contemplated with the same degree of precision. Forexample, for the range 6 to 9, the numbers 7 and 8 are contemplated inaddition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitlycontemplated. In the same manner, all recited ratios also include allsub-ratios falling within the broader ratio.

The singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise.

The term “about” generally refers to a range of numbers that one ofskill in the art would consider equivalent to the recited value (i.e.,having the same function or result). In many instances, the term “about”may include numbers that are rounded to the nearest significant figure.

The term “alkyl” refers to straight chained or branched hydrocarbonswhich are completely saturated. For purposes of exemplification, whichshould not be construed as limiting the scope of this invention,examples of alkyls include methyl, ethyl, propyl, isopropyl, butyl,pentyl, hexyl, and isomers thereof.

The term “alkenyl” refers to a hydrocarbon moiety containing two toeight carbons, including straight chained or branched hydrocarbons whichcontain one or more double bonds. Non-limiting examples of alkenyls areethenyl, propenyl, and butenyl.

The term “amorphous” as applied to a compound refers to a state in whichthe material lacks long range order at the molecular level and,depending upon temperature, may exhibit the physical properties of asolid or a liquid. Typically such materials do not give distinctiveX-ray diffraction patterns and, while exhibiting the properties of asolid, are more formally described as a liquid. Upon heating, a changefrom solid to liquid properties occurs which is characterized by achange of state, typically second order (“glass transition”).

The term “anhydrate” as applied to a compound refers to a solid statewherein the compound contains no structural water within the crystallattice.

The term “aryl” refers to a mono-, bi-, or tricyclic aromatichydrocarbon radical. Examples include phenyl, naphthyl, biphenyl, and1,2,3,4-tetrahydronaphthyl.

Unless the context requires otherwise, the terms “comprise,”“comprises,” and “comprising” are used on the basis and clearunderstanding that they are to be interpreted inclusively, rather thanexclusively, and that Applicant intends each of those words to be sointerpreted in construing this patent, including the claims below.

The term “crystalline” as applied to a compound refers to a solid phasein which the material has a regular ordered internal structure at themolecular level and gives a distinctive X-ray diffraction pattern withdefined peaks. Such materials when heated sufficiently will also exhibitthe properties of a liquid, but the change from solid to liquid ischaracterized by a phase change, typically first order (“meltingpoint”).

The term “crystalline purity” means the crystalline purity of a compoundwith regard to a particular crystalline form of the compound asdetermined by the powder X-ray diffraction analytical methods describedin this application.

The term “crystallization” as used throughout this application can referto crystallization and/or recrystallization depending upon theapplicable circumstances relating to the preparation of the compound.

The term “pharmaceutically acceptable” (such as in the recitation of a“pharmaceutically acceptable salt” or a “pharmaceutically acceptablediluent”) refers to a material that is compatible with administration toa human subject, e.g., the material does not cause an undesirablebiological effect. Examples of pharmaceutically acceptable salts aredescribed in “Handbook of Pharmaceutical Salts: Properties, Selection,and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).Examples of pharmaceutically acceptable excipients are described in the“Handbook of Pharmaceutical Excipients,” Rowe et al., Ed.(Pharmaceutical Press, 7th Ed., 2012).

The term “subject” refers to a human subject.

The terms “treating” and “treatment” refer to ameliorating, suppressing,eradicating, reducing the severity of, decreasing the frequency ofincidence of, preventing, reducing the risk of, slowing the progressionof damage caused by or delaying the onset of the condition or improvingthe quality of life of a patient suffering from the condition.

The term “Xantphos” refers to4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene.

The abbreviation “2-Me THF” refers to 2-methyl tetrahydrofuran.

The abbreviation “ACN” refers to acetonitrile.

The abbreviation “AcOH” refers to acetic acid.

As used herein, the term “AUC_(24,ss)” refers to the steady-state areaunder the plasma concentration time curve from time zero to twenty-fourhours after administration of the referent drug. The term “AUC_(12,ss)”refers to the steady-state area under the plasma concentration timecurve from time zero to twelve hours after administration of thereferent drug.

As used herein, the term “AUC_(inf)” refers to the area under the plasmaconcentration time curve from time zero to infinity following a singledose, calculated using the trapezoidal rule.AUC_(inf)=AUC_(t)+C_(last)/k, where C_(last) is the last measuredconcentration and k is the calculated terminal elimination rateconstant.

As used herein, the term “AUC_(t)” refers to the area under the plasmaconcentration time curve from the time of administration of the referentdrug to the time of the last measured concentration calculated using thetrapezoidal rule. “AUC₂₄” refers to the area under the plasmaconcentration time curve from time zero to twenty-four hours afteradministration of the referent drug following a single dose.

The abbreviation “Bn” refers to benzyl.

As used herein, the term “C₁₂” is the plasma concentration of thereferent drug observed 12 hours after administration of a single dose,or the indicated number of doses, of the referent drug. The term“C_(12,ss)” refers to the C₁₂ as measured at a steady-state.

As used herein, the term “C₂₄” is the plasma concentration of thereferent drug observed 24 hours after administration of a single dose,or the indicated number of doses, of the referent drug. The term“C_(24,ss)” refers to the C₂₄ as measured at a steady-state.

The abbreviation “Cbz” refers to carboxybenzyl.

The abbreviation “CDI” refers to carbonyldiimidazole.

The abbreviation “% CV” refers to the coefficient of variation,expressed as a percent. % CV is calculated according to the followingequation: % CV=(SD/x)*100, wherein x is the mean value and SD is thestandard deviation.

As used herein, the term “C_(max)” refers to the plasma concentration ofthe referent drug at T_(max), expressed herein as ng/mL, produced by theoral ingestion of a single dose, or indicated number of doses, of thedosage form or pharmaceutical composition, such as the dosage forms andcompositions of the present disclosure. Unless specifically indicated,C_(max) refers to the overall maximum observed concentration.

As used herein, the term “C_(max,ss”) refers to the steady-state C_(max)of the referent drug during a dosage interval.

As used herein, the term “C_(min,ss)” refers to the minimum steady-stateplasma concentration of the referent drug during a dosage interval.

As used herein, the term “C_(trough)” refers to the trough plasmaconcentration of the referent drug, as measured at the end of a dosinginterval at steady state.

The abbreviation “DBU” refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.

The abbreviation “DCHA” refers to dicyclohexylamine.

The abbreviation “DCM” refers to dichloromethane.

The abbreviation “DIPEA” refers to diisopropylethylamine.

The abbreviation “DMA” refers to dimethylacetamide, orN,N-dimethylacetamide.

The abbreviation “DMAP” refers to 4-dimethylaminopyridine.

The abbreviation “DSC” means differential scanning calorimetry.

As used herein, the term “entry into a use environment” means contact ofa formulation of the disclosure with the gastric fluids of the subjectto whom it is administered, or with a fluid intended to simulate gastricfluid.

The abbreviation “EtB(OH)₂” refers to ethyl boronic acid.

The abbreviation “EtOAc” refers to ethyl acetate.

The abbreviation “Fe(acac)₃” refers to iron(III) acetylacetonate.

The abbreviation “HDPE” refers to high-density polyethylene.

The abbreviation “HOAc” refers to acetic acid.

The abbreviation “HPMC” refers to hydroxypropyl methylcellulose.

The abbreviation “IPAc” refers to isopropyl acetate.

The abbreviation “KOtBu” refers to potassium tert-butoxide.

The abbreviation LiOtBu” refers to lithium tert-butoxide.

The abbreviation “Me₃SOCl” refers to trimethylsulfoxonium chloride.

The abbreviations “MeOH” and “EtOH” refer to methanol and ethanol,respectively.

The abbreviation “MS” means mass spectrometry.

The abbreviation “MTBE” refers to methyl tert-butyl ether.

The abbreviation “MTX” refers to methotrexate.

The abbreviations “NatOBu” or “NaOtBu” refer to sodium tert-butoxide.

The abbreviation “Ni(acac)₂” refers to nickel (II) acetylacetonate.

The abbreviation “NMM” refers to N-methyl morpholine.

The abbreviation “Pd/C” refers to palladium on carbon.

The abbreviation “PdCl₂(dppf)” refers to[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).

The abbreviation “PdCl₂(Ph₃P)₂” refers tobis(triphenylphosphine)palladium(II) dichloride.

The abbreviation “Pd(OAc)₂” refers to palladium (II) acetate.

The abbreviation “Pd(OH₂)/C” refers to palladium hydroxide on carbon.

The abbreviation “PFPAA” refers to pentafluoropropionic anhydride.

The abbreviation “pTsOH” refers to p-toluenesulfonic acid.

The abbreviation “PVA” refers to polyvinyl acetate.

The abbreviation “PXRD” means powder X-ray diffraction.

The abbreviation “(S)-Segphos Ru(OAc)₂” or “Ru(OAc)₂—Segphos” refers todiacetato[(S)-(−)5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole]ruthenium(II).

As used herein, the term “t_(1/2)” refers to the terminal half-life ofthe referent drug after oral ingestion of a single dose, or indicatednumber of doses, of the referent drug. The term “t_(1/2,ss)” refers tothe terminal half-life as measured at a steady-state.

The abbreviation “TEA” refers to triethylamine.”

The abbreviation “TFAA” refers to trifluoroacetic anhydride.

The abbreviation “TF₂O” refers to trifluoromethanesulfonic anhydride.

The abbreviation “TGA” means thermogravimetric analysis.

The abbreviation “TGA-MS” means thermogravimetric analysis-massspectrometer.

The abbreviation “THF” refers to tetrahydrofuran.

As used herein, the term “T_(max)” refers to the time to peak plasmaconcentration of the referent drug after oral ingestion of a singledose, or indicated number of doses, of the referent drug.

As used herein, the term “T_(max,ss)” refers to the time to peak plasmaconcentration of the referent drug after oral ingestion of the referentdrug at steady-state.

The abbreviation “TMS” refers to trimethylsilyl.

The term “triflate” refers to trifluoromethanesulfonate.

The abbreviation “v/v” refers to volume/volume.

The abbreviation “w/w” refers to weight/weight.

For clarity and convenience purposes only, the convention is utilizedherein of designating the time of drug administration or initiation ofdissolution testing as zero (0) hours (t=0 hours) and times followingadministration in appropriate time units, for example, t=30 minutes ort=2 hours, etc.

II. PROCESSES FOR PREPARING(3S,4R)-3-ETHYL-4-(3H-IMIDAZO[1,2-A]PYRROLO[2,3-E]PYRAZIN-8-YL)-N-(2,2,2-TRIFLUOROETHYL)PYRROLIDINE-1-CARBOXAMIDE(COMPOUND 1) AND INTERMEDIATES

The present disclosure relates to improved processes for preparing(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(referred to herein as “Compound 1” or as “Compound 1 freebase”), topharmaceutically acceptable salts of Compound 1, and to intermediatesused in the preparation of Compound 1. Compound 1 has the structureshown below:

Methods for making and using this compound are described, for example,in International Application WO 2011/068881A1, which is incorporated byreference in this application.

Previously disclosed processes for preparing Compound 1, andpharmaceutically acceptable salts thereof suffer from several drawbacks.In particular, these processes involve the use of particularly hazardousreagents, such as trimethylsilyldiazomethane or diazomethane, and/or donot produce a crystalline product. The processes of the presentdisclosure overcome these drawbacks by avoiding the use of thesehazardous reagents, and producing crystalline intermediates, which aidin purification.

Compounds of the present disclosure may be prepared using synthetictransformations such as those illustrated in Schemes I-XVI. Startingmaterials are commercially available, may be prepared by the proceduresdescribed herein, by literature procedures, or by procedures that wouldbe well known to one skilled in the art of organic chemistry (see, forexample, Larock, R. C. “Comprehensive Organic Transformations: A Guideto Functional Group Preparations, 2^(nd) edition”, 1999, Wiley-VCH orGreene, T. W. and Wuts, P. G. M. “Protective Groups in OrganicSynthesis, 3^(rd) Edition”, 1999, Wiley-Interscience).

A. Preparation of Compound 1

In one aspect, the present disclosure is directed to a process forpreparing Compound 1, or a pharmaceutically acceptable salt thereof. Aprocess for preparing Compound 1 is illustrated in Scheme I. Reaction ofprotected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid (I) or apharmaceutically acceptable salt thereof with trimethylsulfoxoniumchloride gives sulfur ylide (II). Contacting sulfur ylide (II) with LiXand a sulfonic acid yields the corresponding halomethyl ketone (III).Reaction of (III) with (IV) in the presence of a base yields (V).Cyclization of (V) in the presence of a perfluoro acid anhydride and anorganic base produces (VI). Removal of the protecting group andcontacting the deprotected compound with an acid yields apharmaceutically acceptable salt of (VII). Reacting the pharmaceuticallyacceptable salt of (VII) with 2,2,2-trifluoroethylamine producesCompound 1.

wherein:

-   -   PG is a protecting group;    -   X is Br or Cl;    -   R₁ is selected from the group consisting of alkyl, aryl, and        —OR₂;    -   R₂ is alkyl; and    -   Ts is tosyl.

The protecting group may be any suitable protecting group known in theart. In some embodiments, the protecting group is selected from thegroup consisting of carboxybenzyl, p-methoxybenzyl carbonyl, benzyl,p-methoxybenzyl, and 3,4-dimethoxyenzyl. In another embodiment, theprotecting group is carboxybenzyl.

In another embodiment, R₁ is —OR₂, and R₂ is methyl or ethyl. In suchembodiments, the compound of formula (IV) is a compound of formula(IVa):

wherein R₂ is methyl or ethyl. It has surprisingly been discovered thatwhen R₂ is ethyl or methyl, the compound of formula (V) and subsequentdownstream compounds can be isolated as crystalline solids, which aidsin purification of these intermediates. In contrast, previously knownprocesses, which use compounds where R₂ is t-butyl, result in formationof compounds of formula (V) which are isolated as amorphous solids.

In certain embodiments, a pharmaceutically acceptable salt of a compoundof the compound of formula (I) is used in the reaction of step (a). Inone embodiment, the pharmaceutically acceptable salt of the compound offormula (I) is selected from the group consisting of the naphthaleneethane amine salt (Ia) and the dicyclohexylamine salt (Ib)

wherein Cbz is carboxybenzyl.

In one embodiment, the pharmaceutically acceptable salt of compound(VII) is selected from the group consisting of (VIIa), (VIIb), and(VIIc)

Another process for preparing Compound 1 is illustrated in Scheme Ia.Reaction of(3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylatedicyclohexylamine salt (Ib) with trimethylsulfoxonium chloride in thepresence of carbonyldiimidazole and a strong base gives sulfur ylide(IIa). Contacting sulfur ylide (IIa) with lithium bromide and a sulfonicacid yields the corresponding bromomethyl ketone (IIIa). Reaction of(IIIa) with alkyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (IVa)in the presence of lithium tert-butoxide yields (Va). Cyclization of(Va) in the presence of a perfluoro acid anhydride and an organic baseproduces (VIa). Removal of the carboxybenzyl protecting group andcontacting the deprotected compound with hydrochloric acid yields thepharmaceutically acceptable salt (VIIa). Reacting the pharmaceuticallyacceptable salt (VIIa) with 2,2,2-trifluoroethylamine produces Compound1.

wherein:

Cbz is carboxybenzyl;

Ts is tosyl; and

R₂ is methyl or ethyl.

The reaction in step (a) of Schemes I and Ia is generally accomplishedin the presence of a coupling agent, such as carbonyldiimidazole (CDI),and a strong base. The strong base may be, for example, potassiumtert-butoxide, sodium tert-butoxide, or combinations thereof. The step(a) reaction may be conducted in any suitable solvent including, but notlimited to, tetrahydrofuran, water, and methyl tert-butyl ether. In oneembodiment, the reaction is conducted in the presence ofcarbonyldiimidazole and potassium tert-butoxide.

More particularly, in certain embodiments, a solution of a compound offormula (I), (Ia), or (Ib) in solvent is slowly added (e.g., over 30minutes) to a slurry of CDI in solvent, and the resulting mixture isstirred at room temperature for 30 minutes to 12 hours, and typicallyfor about 1 hour. The resulting solution is slowly added (e.g., over 15minutes) to a suspension of the trimethylsulfoxonium chloride, strongbase, and solvent, while maintaining the internal temperature below −1°C. In another embodiment, the reaction is quenched and the resultingcompound of formula (II) or (IIa) is isolated prior to step (b).

In some embodiments, the reaction of step (a) may further involvecontact of (Ia) or (Ib) with an acid prior to reaction with thetrimethylsulfoxonium chloride, in order to extract the amine to obtain acompound of formula (I). Suitable acids include any mineral acid ororganic acid, such as phosphoric acid, hydrochloric acid (HCl), aceticacid (HOAc), citric acid, and the like. The compound of formula (I) maysubsequently be taken up in a suitable solvent, and reacted withtrimethylsulfoxonium chloride, as described herein. In one embodiment, apharmaceutically acceptable salt of a compound of formula (I) is used instep (a), wherein the pharmaceutically acceptable salt is (Ia) or (Ib),and the reaction of step (a) is conducted according to the procedure setforth in Step A of Example 3.

In step (b) of Schemes I and Ia, a compound of formula (II) or (IIa) iscontacted with LiX and a sulfonic acid to form a compound of formula(III) or (IIIa), respectively. In one embodiment, the sulfonic acid isselected from the group consisting of methanesulfonic acid andp-toluenesulfonic acid. In one embodiment, the sulfonic acid isp-toluenesulfonic acid. LiX may be selected from lithium bromide andlithium chloride. In one embodiment, LiX is lithium bromide. In oneembodiment, the reaction is conducted in lithium bromide andp-toluenesulfonic acid. The reaction of step (b) may be conducted in anysuitable solvent including, but not limited to tetrahydrofuran, ethylacetate, heptanes, ethanol, water, and combinations thereof.

More particularly, in certain embodiments, the sulfonic acid is added toa solution of the compound of formula (II) or (IIa) and LiX in asolvent. The resulting mixture is warmed to about 35° C. to about 65° C.and stirred overnight. In one embodiment, the mixture is warmed to about40° C. and stirred overnight. The mixture is cooled to room temperatureand washed. The compound of formula (III) or (IIIa) may be isolated, oroptionally used in the next step without purification.

In step (c) of Schemes I and Ia a compound of formula (III) or (IIIa)are reacted with a compound of formula (IV) or (IVa) (prepared asdescribed herein). The step (c) reaction is conducted in the presence ofa base, such as lithium tert-butoxide, sodium tert-butoxide, orcombinations thereof. In one embodiment, the base is lithiumtert-butoxide. The reaction of step (c) may be conducted in any suitablesolvent including, but not limited to dimethylacetamide,tetrahydrofuran, dichloromethane, ethyl acetate, heptanes, andcombinations thereof.

More particularly, in certain embodiments, the base is added to a cooledsuspension of the compound of formula (III) or (IIIa) in a solvent. Theresulting solution is stirred for about 30 minutes to about 12 hours, orabout 30 minutes, and cooled to about −20° C. to about 0°, or about −10°C. In one embodiment, the solution is stirred for about 30 minutes andcooled to about −20° C. to about 0°. A solution of a compound of formula(IV) or (IVa) in a solvent is slowly added (e.g., over 30 minutes), andthe resulting mixture is stirred for about 30 minutes to about 6 hours,or about 30 minutes, at a temperature of about −20° C. to about 0° C.,or about −10° C. In one embodiment, following addition of the solutionof the compound of formula (IV) or (IVa) in a solvent, the resultingmixture is stirred for about 30 minutes at a temperature of about −10°C. In one embodiment, the reaction is quenched, and, in someembodiments, the resulting product (V) or (Va) is isolated prior to step(d).

In step (d) of Schemes I and Ia, a compound of formula (V) or (Va) iscontacted with a perfluoro acid anhydride and an organic base to form acompound of formula (VI) or (VIa), respectively. Non-limiting examplesof suitable organic bases include pyridine, triethylamine, andcombinations thereof. Examples of suitable perfluoro acid anhydridesinclude trifluoroacetic anhydride, pentafluoropropionic anhydride,heptafluorobutyric anhydride, and combinations thereof. In certainembodiments, the organic base is pyridine and the perfluoro acidanhydride is trifluoroacetic anhydride. In other embodiments, theorganic base is triethylamine, and the perfluoro acid anhydride ispentafluoropropionic anhydride. Suitable solvents for use in step (d)include, but are not limited to acetonitrile, toluene, and combinationsthereof.

More particularly, in certain embodiments, the organic base and theperfluoro acid anhydride are charged into a solution of a compound offormula (V) or (Va) in solvent. The resulting mixture is warmed to about55° C. to about 75° C., or about 55° C., and stirred for about 4 hoursto about 18 hours, or about 6 hours. In one embodiment, the mixture ofperfluoro acid anhydride and the compound of formula (V) or (Va) iswarmed to about 55° C. and stirred for about 4 hours to about 18 hours.In one embodiment, the mixture is stirred for about 6 hours. Uponcompletion of the reaction, in some embodiments, the reaction mixturemay be cooled, and concentrated prior to contacting with a hydroxidesolution to quench excess reagents, and remove the tosyl protectinggroup. Suitable hydroxide solutions include a sodium hydroxide (NaOH)solution, a potassium hydroxide (KOH) solution, and the like. Theresulting mixture may be stirred at room temperature to about 85° C.,including at about 55° C., for about 30 minutes to about 8 hours. In oneembodiment, the mixture is stirred for about 1 hour. Upon completion,the solvent may optionally be removed and switched to methanol, ethanol,isopropanol, or other suitable solvents prior to step (e).

In step (e) of Schemes I and Ia, a compound of formula (VI) or (VIa) isdeprotected, and a pharmaceutically acceptable salt of compound (VII),such as (VIIa), (VIIb), or (VIIc) is formed. The protecting group on thecompound of formula (VI) or (VIa) may be removed using any suitablemeans known in the art. In one embodiment, deprotection occurs bycontacting the compound of formula (VI) or (VIa) with palladium oncarbon (e.g., Pd/C or Pd(OH₂)/C) under hydrogen pressure. In otherembodiments, deprotection occurs by contacting the compound of formula(VI) or (VIa) with an acid. Non-limiting examples of suitable acidsinclude hydrochloric acid (HCl), hydrobromic acid (HBr), hydrobromicacid in acetic acid (e.g., HBr/HOAc), and the like. In otherembodiments, deprotection occurs by subjecting the compound of formula(VI) or (VIa) to heating, e.g., at a temperature of from roomtemperature to about 85° C., including about 50° C. Upon deprotection,the compound of formula (VII) is contacted with the appropriate acid(e.g., hydrochloric acid or p-toluenesulfonic acid) to form thepharmaceutically acceptable salt.

Step (e) may occur in any suitable solvent including, but not limited toethanol, isopropyl acetate, ethyl acetate, and combinations thereof.

More particularly, in some embodiments, palladium on carbon and thecompound of formula (VI) or (VIa) in solvent are mixed under hydrogenpressure at about 1 psig to about 100 psig. In another embodiment, thehydrogen pressure is about 20 psig. The mixture is agitated for about 2hours to about 24 hours, including about 16 hours, at about 20° C. toabout 85° C., including about 50° C. In one embodiment, the mixture isagitated for about 16 hours at about 20° C. to about 80° C. In oneembodiment, the mixture is agitated for about 16 hours at about 50° C.Upon completion of the reaction, the reaction mixture is cooled andfiltered, followed by addition of the appropriate acid. The resultingsalt is optionally isolated prior to step (f).

In step (f), the salt produced in step (e) is reacted with2,2,2-trifluoroethylamine to produce Compound 1. The step (f) reactionis conducted in the presence of a coupling agent, such ascarbonyldiimidazole (CDI), and optionally buffers, such as dipotassiumphosphate, potassium hydroxide, and combinations thereof. In oneembodiment, the step (f) reaction is conducted in the presence of CDI,dipotassium phosphate, and potassium hydroxide. The step (f) reactionmay be conducted in any suitable solvent including, but not limited to,tetrahydrofuran, ethyl acetate, heptanes, ethanol, water, andcombinations thereof.

More particularly, in certain embodiments, 2,2,2-trifluoroethyl amine isadded slowly (e.g., over 20 minutes) to a slurry of CDI in solvent,while maintaining an internal temperature of less than 30° C. Theresulting solution is stirred for about 10 minutes to about 12 hours,and in one embodiment for about 1 hour, to form an imidazolide solution.The pH of a biphasic mixture of the pharmaceutically acceptable saltfrom step (e) in buffer and solvent is adjusted to about 7 to about 11,and in one embodiment to about 9, by addition of a base. The imidazolidesolution is added, and the resulting mixture is mixed at about 25° C.while maintaining a pH of about 9 by portionwise addition of base forabout 30 minutes to about 18 hours. In one embodiment, the mixtureformed after addition of the imidazolide solution is mixed at about 25°C. while maintaining a pH of about 9 by portionwise addition of base forabout 1 hour. In one embodiment, upon completion, the reaction isquenched and the resulting product isolated.

In one embodiment, Compound 1 is prepared according to the process setforth in Scheme Ia. In certain embodiments, the process may furthercomprise preparation of (Ib) according to the process set forth inScheme V herein.

An alternate process for preparing Compound 1 is illustrated in SchemeII. Reaction of protected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid(I) or a pharmaceutically acceptable salt thereof withtrimethylsulfoxonium chloride gives sulfur ylide (II). Contacting sulfurylide (II) with LiX and a sulfonic acid yields the correspondinghalomethyl ketone (III). Reaction of (III) with (IV) in the presence ofa base yields (V). Cyclization of (V) in the presence of a perfluoroacid anhydride and an organic base produces (VI). Removal of theprotecting group and contacting the deprotected compound (VII) (notshown) with hydrochloric acid yields pharmaceutically acceptable salt(VIIb). The pharmaceutically acceptable salt (VIIb) is converted to thefreebase (VII), which is reacted with 2,2,2-trifluoroethylamine toproduce Compound 1. Compound 1 is contacted with L-tartaric acid to formthe corresponding tartrate salt, followed by formation of the Compound 1freebase.

wherein PG, Ts, X, and R₁ are as defined above.

The protecting group may be any suitable protecting group known in theart. In some embodiments, the protecting group is selected from thegroup consisting of carboxybenzyl, p-methoxybenzyl carbonyl, benzyl,p-methoxybenzyl, and 3,4-dimethoxyenzyl. In one embodiment, theprotecting group is carboxybenzyl.

In one embodiment, R₁ is —OR₂, and R₂ is ethyl or methyl.

In certain embodiments, a pharmaceutically acceptable salt of thecompound of formula (I) is used in the reaction of step (a). In oneembodiment, the pharmaceutically acceptable salt of the compound offormula (I) is selected from the group consisting of the naphthaleneethane amine salt (Ia) and the dicyclohexylamine salt (Ib).

Steps (a)-(e) of Scheme II are conducted as described above for SchemeI, wherein following deprotection of the compound of formula (VI),deprotected compound (VII) is contacted with hydrochloric acid to formpharmaceutically acceptable salt (VIIb).

In step (f) of Scheme II, salt (VIIb) is contacted with a base to formthe corresponding freebase (VII). Suitable bases include, but are notlimited to hydroxides, such as sodium hydroxide, potassium hydroxide,and the like, and combinations thereof. In one embodiment, the base issodium hydroxide. The reaction of step (f) may be conducted in anysuitable water-containing solvent including, but not limited to, wateralone or in combination with THF, 2-methyl tetrahydrofuran, ethanol,methanol, and the like.

In step (g) compound (VII) is reacted with 2,2,2-trifluoroethylamine toproduce Compound 1. The step (g) reaction is conducted in the presenceof a coupling agent, such as CDI. Step (g) in Scheme II is conductedusing similar reagents and under similar conditions as those set forthabove for step (f) of Scheme I.

In step (h) of Scheme II, Compound 1 is contacted with L-tartaric acidto form the corresponding tartrate salt (step (h)). Formation of thetartrate salt advantageously aids in removal of impurities prior toisolation of the freebase. In one embodiment, the tartrate salt may beformed using the procedure described in Example 8, Method B, onlywithout drying the tartrate salt prior to step (i). The tartrate salt issubsequently converted back to the freebase form (step (i)) to produceCompound 1. In particular, in step (i) the tartrate salt may becontacted with a base, such as an inorganic base, to produce thecorresponding freebase. Suitable bases include, but are not limited to,sodium bicarbonate, sodium carbonate, sodium hydroxide, potassiumcarbonate, potassium bicarbonate, potassium hydroxide, and the like, orcombinations thereof. In one embodiment, the tartrate salt is contactedwith sodium bicarbonate and sodium carbonate to produce thecorresponding freebase.

Suitable solvents for use in step (h) include, but are not limited to,isopropyl acetate, methyl tert-butyl ether, water, isopropyl alcohol,and combinations thereof. Suitable solvents for use in step (i) include,but are not limited to, ethyl acetate, ethanol, water, and combinationsthereof.

In some embodiments, the products of steps (d), (e), (g), and (h) ofScheme II are not isolated prior to the subsequent step.

An alternate process for preparing Compound 1 is illustrated in SchemeIII. Compound (XIa) is hydrogenated to produce (I). Reaction ofprotected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid (I) withtrimethylsulfoxonium chloride gives sulfur ylide (II). Contacting sulfurylide (II) with an anhydrous source of HBr or HCl yields thecorresponding halomethyl ketone (III). Reaction of (III) with (IV) inthe presence of a base yields (V). Cyclization of (V) in the presence ofa perfluoro acid anhydride and an organic base produces (VI). Removal ofthe protecting group and contacting the deprotected compound with anacid yields a pharmaceutically acceptable salt of (VII). Reacting thepharmaceutically acceptable salt of (VII) with 2,2,2-trifluoroethylamineproduces Compound 1.

wherein:

PG is a protecting group;

X is Br or Cl;

R₁ is selected from the group consisting of alkyl, aryl, and —OR₂;

R₂ is alkyl; and

Ts is tosyl.

The protecting group may be any suitable protecting group known in theart. In some embodiments, the protecting group is selected from thegroup consisting of carboxybenzyl, p-methoxybenzyl carbonyl, benzyl,p-methoxybenzyl, and 3,4-dimethoxyenzyl. In another embodiment, theprotecting group is carboxybenzyl.

In another embodiment, R₁ is —OR₂, and R₂ is methyl or ethyl. In suchembodiments, the compound of formula (IV) is a compound of formula(IVa):

wherein R₂ is methyl or ethyl. It has surprisingly been discovered thatwhen R₂ is ethyl or methyl, the compound of formula (V) and subsequentdownstream compounds can be isolated as crystalline solids, which aidsin purification of these intermediates. In contrast, previously knownprocesses, which use compounds where R₂ is t-butyl, result in formationof compounds of formula (V) which are isolated as amorphous solids.

Another process for preparing Compound 1 is illustrated in Scheme Ma.1-((benzyloxy)carbonyl)-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid(XI) is hydrogenated to produce (XII). Reaction of(3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate (XII)with trimethylsulfoxonium chloride gives sulfur ylide (IIa). Contactingsulfur ylide (IIa) with an anhydrous source of HBr yields thecorresponding bromomethyl ketone (IIIa). Reaction of (IIIa) with alkyl5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-ylcarbamate (IVa) in the presence oflithium tert-butoxide yields (Va). Cyclization of (Va) in the presenceof a perfluoro acid anhydride and an organic base produces (VIa).Removal of the carboxybenzyl protecting group and contacting thedeprotected compound with hydrochloric acid yields the pharmaceuticallyacceptable salt (\Ma). Reacting the pharmaceutically acceptable salt(VIIa) with 2,2,2-trifluoroethylamine produces Compound 1.

wherein:

Cbz is carboxyben zyl;

Ts is tosyl; and

R₂ is methyl or ethyl.

In step (a) of Schemes III and Ma, (XIa) or (XI) (which may be preparedas described in Scheme V) is converted to (I) or (XII), respectively. Inparticular, in step (a), compound (XI) or (XIa) may be contacted with acatalyst, such as a ruthenium catalyst. Any catalyst comprising a chiralphosphine may be used. One particular example of a suitable catalyst isdiacetato[(S)-(−)5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole]ruthenium(II)(i.e., (S)-Segphos Ru(OAc)₂). Suitable solvents for use in step (a)include, but are not limited to, methanol, triethylamine, andcombinations thereof.

In particular, in certain embodiments, a solution of (XI) or (XIa) andthe catalyst in solvent is hydrogenated at about 30° C. to about 100° C.for from about 1 hour to about 18 hours. In one embodiment, the solutionof (XI) or (XIa) and the catalyst in solvent is hydrogenated at about580 psi. In one embodiment, the solution of (XI) or (XIa) and thecatalyst in solvent is hydrogenated at about 200 psi gauge (psig). Inone embodiment, the solution of (XI) or (XIa) and the catalyst insolvent is hydrogenated at about 80° C. for from about 1 hour to about 8hours, or for about 2 hours, or for about 4 hours. Upon completion, thereaction mixture is cooled to room temperature, filtered, andconcentrated. In one particular embodiment, step (a) of Schemes III andMa is performed as described in Step A of Example 4.

The reaction in step (b) of Schemes III and Ma, is generallyaccomplished in the presence of a coupling agent, such ascarbonyldiimidazole (CDI), and a strong base. The strong base may be,for example, potassium tert-butoxide, sodium tert-butoxide, orcombinations thereof. The step (b) reaction may be conducted in anysuitable solvent including, but not limited to, tetrahydrofuran, water,and methyl tert-butyl ether. In one embodiment, the reaction isconducted in the presence of carbonyldiimidazole and potassiumtert-butoxide.

More particularly, in certain embodiments, a suspension oftrimethylsulfoxonium chloride, strong base, and solvent is heated (e.g.,to about 35° C. to about 65° C., or to about 45° C.) for about 30minutes to about 8 hours, or for about 1 hour, followed by cooling. Inone embodiment, the suspension is cooled to a temperature of about −1°C. or less, or to about −5° C. or less. In some embodiments, theconcentrated filtrate from step (a) is diluted with a suitable solvent(e.g., tetrahydrofuran), and to this solution is slowly added (e.g.,over 30 minutes to 1 hour, or over 30 minutes) CDI. The resultingmixture is stirred at room temperature for 30 minutes to 12 hours, andtypically for about 1 hour. The resulting solution is slowly added(e.g., over 15 minutes to 1 hour, or over 1 hour) to the suspension ofthe trimethylsulfoxonium chloride, strong base, and solvent, whilemaintaining the internal temperature below −1° C. In embodiments, thereaction may be stirred for about 30 minutes to about 8 hours, or forabout 1 hour at a temperature of below about −1° C., or at about −5° C.In another embodiment, the reaction is quenched and the resultingcompound of formula (II) or (IIa) is isolated prior to step (c). In oneparticular embodiment, step (b) of Schemes III or Ma is performed asdescribed in Step A of Example 4.

Steps (a) and (b) of Schemes III and Ma advantageously allow forpreparation of a protected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acidwithout formation and isolation of the naphthalene ethane amine salt(Ia) or the dicyclohexylamine salt (Ib), or isolation of (I) or (XI).

In step (c) of Schemes III and IIIa, a compound of formula (II) or (IIa)is contacted with an anhydrous source of HBr or HCl to form a compoundof formula (III) or (IIIa), respectively. In particular, the anhydroussource of HBR or HCl comprises no more than 0.2% water (by volume), orno more than about 0.15% water (by volume). The reaction of step (c) maybe conducted in any suitable solvent including, tetrahydrofuran.

More particularly, in certain embodiments, (II) or (IIa) is combinedwith the HBr or HCl in a suitable solvent. In one embodiment, thesolvents are tetrahydrofuran and acetic acid. In one embodiment, thesolvent comprises no more than 0.2% water (by volume). In oneembodiment, (II) or (IIa) is combined with a solvent (e.g., THF) and asolution of HBr in HOAc. The resulting mixture is warmed to about 35° C.to about 65° C., or about 40° C. and agitated. In one embodiment, themixture is agitated for about 4 to about 12 hours, or for about 5 hours.In one embodiment, the mixture is warmed to about 40° C. and agitated(e.g., stirred) for about 5 hours. In one embodiment, the mixture iscooled to room temperature (e.g., around 20° C.) and distilled, followedby washing. In one particular embodiment, the product (compound (III) or(IIIa)) is concentrated to dryness, and resuspended in a solvent (e.g.,N,N-dimethylacetamide) to form a solution of (III) or (IIIa) for use instep (d). In one embodiment, step (c) of Schemes III or Ma is performedas described in Step B of Example 4.

Step (c) advantageously produces the halomethyl ketone (III) or (IIIa)in higher purity than Scheme I or Ia.

In step (d) of Schemes III and IIIa, a compound of formula (III) or(IIIa) is reacted with a compound of formula (IV) or (IVa) (prepared asdescribed herein). The step (d) reaction is conducted in the presence ofa base, such as lithium tert-butoxide, sodium tert-butoxide, orcombinations thereof. In one embodiment, the base is lithiumtert-butoxide. The reaction of step (d) may be conducted in any suitablesolvent including, but not limited to dimethylacetamide,tetrahydrofuran, dichloromethane, ethyl acetate, heptanes, andcombinations thereof.

More particularly, in certain embodiments, the base is slowly added(e.g., over about 30 minutes) to a cooled suspension of the compound offormula (IV) or (IVa) in a solvent.

In one embodiment, the suspension of the compound of formula (IV) or(IVa) is cooled to about 0° C. The resulting solution is stirred forabout 30 minutes to about 12 hours, or about 30 minutes, and cooled toabout −20° C. to about 0° C., or about −10° C. In one embodiment, thesolution is stirred for about 30 minutes and cooled to about −20° C. toabout 0° C., or about −10° C. The halomethyl ketone solution prepared instep (c) is then slowly added (e.g., over about 1 hour), and theresulting mixture is agitated (e.g., stirred) for about 30 minutes toabout 6 hours, or about 30 minutes, at a temperature of about −20° C. toabout 0° C., or about −10° C. In one embodiment, following addition ofthe step (c) solution, the resulting mixture is stirred for about 30minutes at a temperature of about −10° C. In one embodiment, thereaction is quenched, and, in some embodiments, the resulting product(V) or (Va) is isolated prior to step (e). In one embodiment, step (d)of Schemes III and Ma is performed as described in Step C of Example 4.

Steps (e)-(g) of Schemes III and Ma may be conducted as described abovefor steps (d)-(f) of Scheme I, respectively.

In one embodiment, Compound 1 is prepared according to the process setforth in Scheme IIIa.

B. Preparation of compounds of formula (I), (Ia), (Ib), and (XIa)

The processes for preparing Compound 1 disclosed herein may use acompound of formula (I), or a pharmaceutically acceptable salt thereof,and/or a compound of formula (XI) or (XIa). In one embodiment, theprocesses use either the naphthalene ethane amine salt of formula (Ia),or the dicyclohexylamine salt of formula (Ib). Compounds of formula (I)and (Ia) and their preparation are described in, for example, US2013/0072470, which is herein incorporated by reference. (Ia) can alsobe prepared as described in Scheme IV, set forth below. (Ib) can beprepared as described in Scheme V, set forth below. Compounds of formula(I) wherein PG is Cbz (i.e., compounds of formula (XII)) can be preparedusing the procedure set forth in Scheme IV or V. Compounds of formula(XI) can be prepared using the procedure set forth in Scheme V. Otherprotecting groups may be substituted for Cbz using techniques known tothose skilled in the art.

Formula (Ia)

The preparation of (Ia) has been previously described (see, e.g., US2013/0072470, Example 12, which is herein incorporated by reference).One suitable process for preparing the naphthalene ethane amine salt ofthe compound of formula (I) is illustrated in Scheme IV. Ethylpent-2-ynoate is hydrogenated with a Lindlar catalyst to form (Z)-ethylpent-2-enoate. The (Z)-ethyl pent-2-enoate is reacted withN-(methoxymethyl)-N-(trimethylsilyl methyl)benzylamine to form (XIII).(XIII) is deprotected to form (XIV), followed by hydrolysis of (XIV) toform (XV). (XV) is reacted with N-(benzyloxycarbonyloxy) succinimide toform (XVI). The protected (XVI) is contacted with(R)-1-(naphthalene-1-yl)ethanamine to form (Ia).

wherein:

-   -   TMS is trimethylsilyl;    -   Cbz is carboxybenzyl; and    -   Bn is benzyl.

In step (a) of Scheme IV, ethyl pent-2-ynoate is hydrogenated with aLindlar catalyst to form (Z)-ethyl pent-2-enoate. In particular, incertain embodiments, the ethyl pent-2-ynoate is added to a slurry of theLindlar catalyst in solvent (e.g., THF) and organic base (e.g.,pyridine). The reaction mixture is sparged with hydrogen (e.g., forabout 15 hours). In one embodiment, upon reaction completion, thereaction mixture is filtered, and the (Z)-ethyl pent-2-enoate washedprior to step (b).

In step (b) of Scheme IV, the (Z)-ethyl pent-2-enoate is reacted withN-(methoxymethyl)-N-(trimethylsilyl methyl)benzylamine to form (XIII).In particular, trifluoroacetic acid (TFA) is added to a solution of the(Z)-ethyl pent-2-enoate and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine in solvent (e.g., dichloromethane (DCM)). After about2 days, the reaction mixture is concentrated to provide (XIII).

In steps (c) and (d) of Scheme IV, (XIII) is deprotected to form (XIV),followed by hydrolysis of (XIV) to form (XV). (XIII) may be deprotectedusing any suitable means known in the art, including those set forthabove for step (e) of Scheme I. In one embodiment, (XIII) is deprotectedby contacting (XIII) with a catalyst (e.g., a palladium catalyst such asPd/C or Pd(OH₂)/C) under hydrogen pressure. In one embodiment, theresulting mixture is filtered to provide (XIV). In step (d), (XIV) iscontacted with an acid (e.g., HCl). In one embodiment, the reactionmixture is heated (e.g., to about 100° C.), typically for about 24hours. The reaction mixture is cooled and concentrated. In step (e), thereaction mixture from step (d) containing (XV) is reacted withN-(benzyloxycarbonyloxy) succinimide (e.g., for about 15 hours) to form(XVI).

In step (f) of Scheme IV, (XVI) is contacted with(R)-1-(naphthalene-1-yl)ethanamine to form (Ia).

Formula (Ib)

In some embodiments, the present disclosure is directed to compound (Ib)and a process for preparing compound (Ib). A process for preparing thedicyclohexylamine salt of the compound of formula (I) is illustrated inScheme V. Carboxybenzyl-glycine ethyl ester is reacted with ethylacrylate to form (VIII). Protection of (VIII) yields (IX). Contacting(IX) with one of ethyl boronic acid, ethyl magnesium bromide, or ethylzinc chloride in the presence of a catalyst results in (X). (X) ishydrolyzed to produce (XI), which is hydrogenated to produce (XII).(XII) is contacted with dicyclohexylamine to form (Ib).

wherein

-   -   Cbz is carboxybenzyl; and    -   R³ is selected from the group consisting of CF₃SO₂—, CH₃SO₂—,        and tosyl.

In step (a) of Scheme V, carboxybenzyl-glycine ethyl ester is reactedwith ethyl acrylate to form (VIII). The step (a) reaction is conductedin the presence of a strong base. Suitable bases include, but are notlimited to, sodium tert-butoxide, potassium tert-butoxide, and lithiumtert-butoxide. In one embodiment, the strong base is sodiumtert-butoxide. In one embodiment, the step (a) reaction is conducted inan organic solvent, such as tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, 2-methyl tetrahydrofuran, and the like, andcombinations thereof.

In particular, in certain embodiments, the base is slowly added (e.g.,over 1 hour) to a mixture of the carboxybenzyl-glycine ethyl ester andethyl acrylate in solvent at about −5° C. to about 20° C. In oneembodiment, the base is slowly added (e.g., over 1 hour) to a mixture ofthe carboxybenzyl-glycine ethyl ester and ethyl acrylate in solvent atabout 0° C. The resulting mixture is warmed to room temperature, andstirred overnight. In one embodiment, upon completion, the reaction isquenched and the product crystallized. The product may optionally beisolated prior to step (b).

In step (b) of Scheme V, the compound of formula (VIII) is protected toform (IX). In one embodiment, the compound of formula (VIII) is reactedwith a reagent selected from the group consisting oftrifluoromethanesulfonic anhydride, methanesulfonyl chloride, andp-toluenesulfonyl chloride to form (IX). In one embodiment, the step (b)reaction is conducted in the presence of an organic base. Suitableorganic bases include, but are not limited to, diisopropylethylamine(DIPEA), 4-dimethylamino pyridine (DMAP), triethylamine (TEA), pyridine,N-methylmorpholine (NMM), and combinations thereof. The step (b)reaction may be conducted in any suitable solvent including, but notlimited to, triethylamine, N-methylmorpholine, pyridine, diisopropylether, and combinations thereof.

In particular, in certain embodiments, the trifluoromethanesulfonicanhydride, methanesulfonyl chloride, or p-toluenesulfonyl chloride isadded to a mixture of (VIII) in solvent at about −5° C. to about 20° C.In one embodiment, the trifluoromethanesulfonic anhydride,methanesulfonyl chloride, or p-toluenesulfonyl chloride is added to amixture of (VIII) in solvent at a temperature of about 0° C. The organicbase is subsequently slowly added (e.g., over about 30 minutes), and themixture warmed to room temperature and stirred for about 30 minutes toabout 18 hours. In one embodiment, the mixture is stirred for about 1hour. Upon completion, the reaction is preferably quenched and theproduct washed. In some embodiments, a solution of (IX) in solvent isprepared and used directly in step (c).

In step (c) of Scheme V, (IX) is contacted with one of ethyl boronicacid, ethyl magnesium bromide, or ethyl zinc chloride in the presence ofa catalyst to produce (X). Any suitable catalyst known in the art may beused. In certain embodiments, the catalyst is a palladium catalyst, suchas PdCl₂(dppf). In some embodiments, the catalyst is a nickel catalyst,such as Ni(acac)₂. In some embodiments, the catalyst is an ironcatalyst, and in particular a Fe(III) catalyst, such as FeCl₃ andFe(acac)₃. Step (c) may be conducted in a buffer. Suitable buffersinclude, but are not limited to, potassium carbonate, sodium carbonate,potassium phosphate tribasic, and combinations thereof. Suitablesolvents for use in step (c) include, but are not limited to, toluene,water, dioxane, tetrahydrofuran, and combinations thereof.

In particular, in certain embodiments, the ethyl boronic acid and bufferis added to the solution of (IX) in solvent prepared in step (b). Asuitable catalyst may then be added, and the resulting mixture warmed toabout 75° C. to about 110° C., or about 85° C., and stirred for about 4hours to about 18 hours, or about 6 hours. In one embodiment, themixture is warmed to about 85° C., and stirred for about 6 hours. Uponcompletion, the reaction mixture is cooled to room temperature, and theproduct filtered. In one embodiment, the product is isolated prior tostep (d).

In step (d), (X) is hydrolyzed to produce (XI). (X) may be hydrolyzedusing any suitable means known in the art. In one embodiment, (X) iscontacted with an alkali metal hydroxide. The alkali metal hydroxide maybe selected from the group consisting of sodium hydroxide and lithiumhydroxide. In one embodiment, the alkali metal hydroxide is sodiumhydroxide. Any suitable solvent may be used in the step (d) reactionincluding, but not limited to, tetrahydrofuran, water, dioxane, andcombinations thereof.

In particular, in certain embodiments, the alkali metal hydroxide isadded to a solution of (X) in solvent. The resulting mixture is warmedto about 20° C. to about 65° C., and stirred for about 2 hours to about18 hours. In one embodiment, the mixture is warmed to about 50° C., andstirred for about 2 hours to about 18 hours. In one embodiment, themixture is stirred for about 7 hours. Upon completion, the mixture iscooled to room temperature, the pH adjusted to about 9, and the solventremoved. In one embodiment, the product is washed and isolated prior tostep (e).

In steps (e) and (f) of Scheme V, (XI) is converted to (XII), and (XII)is contacted with dicyclohexylamine to form (Ib). In particular, in step(e) compound (XI) may be contacted with a catalyst, such as a rutheniumcatalyst. Any catalyst comprising a chiral phosphine may be used. Oneparticular example of a suitable catalyst isdiacetato[(S)-(−)5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole]ruthenium(II)(i.e., (S)-Segphos Ru(OAc)₂). Suitable solvents for use in step (e)include, but are not limited to, methanol, triethylamine, andcombinations thereof.

In particular, in certain embodiments, a solution of (XI) and thecatalyst in solvent is hydrogenated at about 30° C. to about 100° C. forfrom about 1 hour to about 18 hours. In one embodiment, the solution of(XI) and the catalyst in solvent is hydrogenated at about 580 psi. Inone embodiment, the solution of (XI) and the catalyst in solvent ishydrogenated at about 80° C. for from about 1 hour to about 8 hours, orfor about 2 hours. Upon completion, the reaction mixture is cooled toroom temperature, filtered, and concentrated. In one embodiment, theproduct is washed, and transferred to a suitable solvent, such asacetonitrile, prior to step (f). In step (f), additional solvent (e.g.,acetonitrile) and dicyclohexylamine are added, and the mixture is heatedto about 50° C. to about 80° C. In one embodiment, the mixture is heatedto about 80° C. The resulting solution is cooled to room temperature andstirred for about 1 hour to about 18 hours. In one embodiment, themixture is cooled to room temperature and stirred for about 1 hour. Theresulting product (Ib) may be isolated prior to use in preparation ofCompound 1.

C. Intermediate Compounds

In some embodiments, the present disclosure is directed to intermediatecompounds useful in the preparation of Compound 1, as well as toprocesses for preparing the intermediate compounds.

Formula (IVa)

In one embodiment, the present disclosure is directed to a compound offormula (IVa).

wherein R₂ and Ts are as defined above.

As discussed herein and as depicted in Schemes I, II, and III, compoundsof formula (IVa) may be reacted with a compound of formula (III) or(IIIa) to produce a compound of formula (V) or (Va). Advantageously, themethyl or ethyl carbamate moiety present on the compound of formula(IVa) results in a crystalline product when the compound of formula(IVa) is reacted with a compound of formula (III) or (IIIa) in SchemesI, II, or III.

In another aspect, the present disclosure is directed to a process forpreparing a compound of formula (IVa). One suitable process forpreparing a compound of formula (IVa) is illustrated in Scheme VI. Inparticular, (XVII) is reacted with trimethylsilylacetylene in thepresence of a catalyst to form (XVIII). (XVIII) is contacted withp-toluenesulfonyl chloride in the presence of a base to form (XIX).(XIX) is reacted with an ethyl or methyl carbamate in the presence of acatalyst and a ligand to form a compound of formula (IVa).

wherein:

-   -   R₂ is methyl or ethyl;    -   Ts is tosyl; and    -   TMS is trimethylsilyl.

In step (a) of Scheme VI, compound (XVII), which is commerciallyavailable, is reacted with trimethylsilylacetylene in the presence of acatalyst to form (XVIII). Any suitable catalyst known in the art may beused. In some embodiments, the catalyst is a palladium catalyst, such asbis(triphenylphosphine)palladium (II) dichloride (PdCl₂(Ph₃P)₂). Step(a) is typically conducted in the presence of copper (I) iodide (CuI).Any suitable solvent may be used in step (a), including, but not limitedto, triethylamine.

In particular, in certain embodiments, the catalyst is added to asolution of (XVII) and CuI in solvent. The reaction mixture is cooled(e.g., to about −5 to 0° C.), and a solution of thetrimethylsilylacetylene in solvent is slowly added (e.g., over about 15minutes). The reaction mixture is stirred at about −5 to 0° C. (e.g.,for about 1.5 hours), and allowed to warm to room temperature overnight.In one embodiment, the reaction mixture is filtered and washed, and theproduct isolated prior to step (b).

In step (b) of Scheme VI, (XVIII) is contacted with p-toluenesulfonylchloride in the presence of a base to form (XIX). Suitable bases for usein step (b) include, but are not limited to, potassium tert-butoxide,sodium hydride, and the like, and combinations thereof. Suitablesolvents for use in step (b) include, but are not limited to,dimethylformamide.

In particular, in certain embodiments, the base is added to a solutionof (XVIII) in solvent (e.g., at about 0° C.). The p-toluenesulfonylchloride is subsequently added, and the mixture is allowed to warm toroom temperature. After reaction (e.g., for about 16 hours), thereaction mixture is poured into ice cold water, and the precipitate iscollected. In one embodiment, the product is isolated and purified priorto step (c).

In step (c) of Scheme VI, (XIX) is reacted with an ethyl or methylcarbamate in the presence of a catalyst and a ligand to form a compoundof formula (IVa). The reaction may be conducted in the presence ofbuffers, such as potassium carbonate, tetramethylammonium hydroxide, andthe like. Any suitable catalyst known in the art may be used in step(c). In one embodiment, the catalyst is a palladium catalyst, such aspalladium (II) acetate. Suitable ligands for use in step (c) includebidentate ligands, such as Xantphos. In one embodiment, the catalyst ispalladium (II) acetate and the ligand is Xantphos. Suitable solvents foruse in step (c) include, but are not limited to, dioxane, toluene, andtetrahydrofuran.

In particular, in certain embodiments, a degassed mixture of thecatalyst, ligand, (XIX), carbamate, and the buffer in solvent is heatedto about 75° C. to about 110° C., or about 95° C., and stirredovernight. After completion, the reaction mixture is cooled to about 30°C. to about 60° C. In one embodiment, the reaction mixture is cooled toabout 50° C. Optionally, additional solvent may be added, and theresulting solution filtered. In another embodiment, the product iswashed and isolated prior to use in preparation of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Compound (XVII) used in Scheme VI is commercially available. Thepreparation of compounds (XVIII) and (XIX) are also described in Example1 of WO 2011/068881, which is herein incorporated by reference.

Formula (II)

In one aspect, the present disclosure is directed to a compound offormula (II):

wherein PG is a protecting group.

The protecting group may be any suitable protecting group known in theart. In some embodiments, the protecting group is selected from thegroup consisting of carboxybenzyl, p-methoxybenzyl carbonyl, benzyl,p-methoxybenzyl, and 3,4-dimethoxyenzyl.

In one preferred embodiment, the protecting group is carboxybenzyl, andthe compound of formula (II) is compound (IIa):

wherein Cbz is carboxybenzyl.

In another aspect, the present disclosure is directed to a process forpreparing a compound of formula (II) or (IIa). One process for preparinga compound of formula (II) or (IIa) is illustrated in Scheme VII. InScheme VII, a compound of formula (I) or a pharmaceutically acceptablesalt thereof is reacted with trimethylsulfoxonium chloride to form acompound of formula (II). In one particular embodiment, thepharmaceutically acceptable salt is a compound of formula (Ib).

wherein PG is a protecting group as defined herein.

The reaction of Scheme VII is generally accomplished in the presence ofa coupling agent, such as carbonyldiimidazole (CDI), and a strong base.The strong base may be, for example, potassium tert-butoxide, sodiumtert-butoxide, or combinations thereof. The Scheme VII reaction may beconducted in any suitable solvent including, but not limited to,tetrahydrofuran, water, and methyl tert-butyl ether. In one embodiment,the reaction is conducted in the presence of carbonyldiimidazole andpotassium tert-butoxide. In one embodiment, the reaction of Scheme VIIis conducted under the conditions described above for step (a) of SchemeI.

Another process for preparing a compound of formula (II) or (IIa) isillustrated in Scheme VIII. In step (a) of Scheme VIII, a compound offormula (XIa) is hydrogenated to a compound of formula (I), and in step(b) of Scheme VIII, the compound of formula (I) is reacted withtrimethylsulfoxonium chloride to form a compound of formula (II).

wherein PG is a protecting group as defined herein.

In step (a) of Scheme VIII, the compound of formula (XIa) may becontacted with a catalyst, such as a ruthenium catalyst. Any catalystcomprising a chiral phosphine may be used. One particular example of asuitable catalyst isdiacetato[(S)-(−)5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxol]ruthenium(II)(i.e., (S)-Segphos Ru(OAc)₂). Suitable solvents for use in step (a)include, but are not limited to, methanol, triethylamine, andcombinations thereof. In one embodiment, the reaction of step (a) ofScheme VIII is conducted under the conditions described above for step(a) of Scheme III.

The reaction in step (b) of Scheme VIII is generally accomplished in thepresence of a coupling agent, such as carbonyldiimidazole (CDI), and astrong base. The strong base may be, for example, potassiumtert-butoxide, sodium tert-butoxide, or combinations thereof. The step(b) reaction may be conducted in any suitable solvent including, but notlimited to, tetrahydrofuran, water, and methyl tert-butyl ether. In oneembodiment, the reaction is conducted in the presence ofcarbonyldiimidazole and potassium tert-butoxide. In one embodiment, thereaction of step (b) of Scheme VIII is conducted under the conditionsdescribed above for step (b) of Scheme III.

Formula (III)

In another embodiment, the present disclosure is directed to a processfor preparing a compound of formula (III):

wherein PG is a protecting group, and X is Br or Cl.

The protecting group may be any suitable protecting group known in theart. In some embodiments, the protecting group is selected from thegroup consisting of carboxybenzyl, p-methoxybenzyl carbonyl, benzyl,p-methoxybenzyl, and 3,4-dimethoxyenzyl.

In one preferred embodiment, the protecting group is carboxybenzyl and Xis Br, and the compound of formula (III) is compound (IIIa)

wherein Cbz is carboxybenzyl.

One process for preparing a compound of formula (III) or (IIIa) isillustrated in Scheme IX.

wherein PG and X are as defined herein.

Referring to Scheme IX, in one embodiment, a compound of formula (II) iscontacted with LiX and a sulfonic acid to form a compound of formula(III). In this embodiment, the sulfonic acid is selected from the groupconsisting of methanesulfonic acid and p-toluenesulfonic acid. In oneembodiment, the sulfonic acid is p-toluenesulfonic acid. LiX may beselected from lithium bromide and lithium chloride. In one embodiment,LiX is lithium bromide. In one embodiment, the reaction is conducted inlithium bromide and p-toluenesulfonic acid. The reaction may beconducted in any suitable solvent including, but not limited totetrahydrofuran, ethyl acetate, heptanes, ethanol, water, andcombinations thereof. In one embodiment, the reaction of Scheme XI isconducted under the conditions described above for step (b) of Scheme I.

Referring to Scheme IX, in an alternate embodiment, the compound offormula (II) is contacted with an anhydrous source of HBr or HCl to formthe compound of formula (III). The reaction may be conducted in anysuitable solvent including, but not limited to, tetrahydrofuran, ethylacetate, acetic acid, N,N-dimethylacetamide, heptanes, and combinationsthereof. In one embodiment, the reaction of Scheme IX is conducted underthe conditions described above for step (c) of Scheme III.

In some embodiments, the process for preparing a compound of formula(III) or (IIIa) may further comprise preparing a compound of formula(II). One such process is illustrated in Scheme X.

wherein PG and X are as defined above.

In Scheme X, a compound of formula (I) or a pharmaceutically acceptablesalt thereof is reacted with trimethylsulfoxonium chloride in thepresence of carbonyldiimidazole and a strong base (e.g., potassiumtert-butoxide, sodium tert-butoxide, and combinations thereof) to form acompound of formula (II). The compound of formula (II) is then contactedwith LiX and a sulfonic acid to form a compound of formula (III), asdescribed above in Scheme IX. In one embodiment, step (a) of Scheme X isconducted under the conditions described above for step (a) of Scheme I.In one embodiment, the protecting group is carboxybenzyl, and thecompound of formula (II) is compound (IIa). In another embodiment, instep (a) of Scheme X, a pharmaceutically acceptable salt of a compoundof formula (I) is reacted with trimethylsulfoxonium chloride to form acompound of formula (II). In one embodiment, the salt is (Ia) or (Ib).

In some embodiments, the process for preparing a compound of formula(III) or (IIIa) may further comprise preparing a compound of Formula (I)and (II). One such process is illustrated in Scheme XI.

wherein PG and X are as defined above.

In step (a) of Scheme XI, a compound of formula (XIa) is hydrogenated toa compound of formula (I), and in step (b), the compound of formula (I)is reacted with trimethylsulfoxonium chloride in the presence of CDI anda strong base (e.g., KOtBu, NatOBu, and combinations thereof) to form acompound of formula (II). The compound of formula (II) is then contactedwith an anhydrous source of HBr or HCl to form the compound of formula(III), as described above for Scheme IX. In one embodiment, theprotecting group is carboxybenzyl, and the compound of formula (XIa),(I), and (II) is compound (XI), (XII), and (IIa), respectively. In oneembodiment, step (a), step (b), and step (c) of Scheme XI are conductedunder the conditions described above for step (a), step (b), and step(c) of Scheme III, respectively.

Formulae (V) and (Va)

In another embodiment, the present disclosure is directed to a compoundof formula (Va):

wherein R₂, Cbz, and Ts are as defined above.

In another aspect, the present disclosure is directed to a process forpreparing a compound of formula (V) or (Va). One process for preparing acompound of formula (V) or (Va) is illustrated in Scheme XII. In SchemeXII, a compound of formula (I) or a pharmaceutically acceptable saltthereof is reacted with trimethylsulfoxonium chloride to form a compoundof formula (II). Contacting the compound of formula (II) with LiX and asulfonic acid yields the corresponding halomethyl ketone (III). Reactionof a compound of formula (III) with a compound of formula (IV) in thepresence of a base yields a compound of formula (V).

wherein PG, Ts, R₁, and X are as defined above.

The protecting group may be any suitable protecting group known in theart. In some embodiments, the protecting group is selected from thegroup consisting of carboxybenzyl, p-methoxybenzyl carbonyl, benzyl,p-methoxybenzyl, and 3,4-dimethoxyenzyl.

In one embodiment, the protecting group is carboxybenzyl, and thecompound is a compound of formula (Va). In one embodiment, theprotecting group is carboxybenzyl, and X is Br.

In one embodiment, R₁ is —OR₂, and R₂ is methyl or ethyl. In suchembodiments, the compound of formula (IV) is a compound of formula(IVa).

In certain embodiments, a pharmaceutically acceptable salt of a compoundof formula (I) is used in the reaction of step (a) of Scheme XII. In oneembodiment, the pharmaceutically acceptable salt of the compound offormula (I) is selected from the group consisting of the naphthaleneethane amine salt (Ia) and the dicyclohexylamine salt (Ib).

The reaction in step (a) of Scheme XII is generally accomplished in thepresence of a coupling agent, such as carbonyldiimidazole (CDI), and astrong base. The strong base may be, for example, potassiumtert-butoxide, sodium tert-butoxide, or combinations thereof. The step(a) reaction may be conducted in any suitable solvent including, but notlimited to, tetrahydrofuran, water, and methyl tert-butyl ether. In oneembodiment, the reaction is conducted in the presence ofcarbonyldiimidazole and potassium tert-butoxide.

In step (b) of Scheme XII, a compound of formula (II) or (IIa) iscontacted with LiX and a sulfonic acid to form a compound of formula(III) or (IIIa), respectively. In one embodiment, the sulfonic acid isselected from the group consisting of methanesulfonic acid andp-toluenesulfonic acid. In one embodiment, the sulfonic acid isp-toluenesulfonic acid. LiX may be selected from lithium bromide andlithium chloride. In one embodiment, LiX is lithium bromide. In oneembodiment, the reaction is conducted in lithium bromide andp-toluenesulfonic acid. The reaction of step (b) may be conducted in anysuitable solvent including, but not limited to tetrahydrofuran, ethylacetate, heptanes, ethanol, water, and combinations thereof.

In step (c) of Scheme XII, a compound of formula (III) or (IIIa) isreacted with a compound of formula (IV) or (IVa) (prepared as describedherein). The step (c) reaction is conducted in the presence of a base,such as lithium tert-butoxide, sodium tert-butoxide, or combinationsthereof. In one embodiment, the base is lithium tert-butoxide. Thereaction of step (c) may be conducted in any suitable solvent including,but not limited to dimethylacetamide, tetrahydrofuran, dichloromethane,ethyl acetate, heptanes, and combinations thereof.

In one embodiment, steps (a), (b), and (c) of Scheme XII are conductedunder the conditions set forth herein for the corresponding step ofScheme I.

In another aspect, the present disclosure is directed to an alternateprocess for preparing a compound of formula (V) or (Va). One process forpreparing a compound of formula (V) or (Va) is illustrated in SchemeXIII. In Scheme XIII, a compound of formula (XIa) is hydrogenated to acompound of formula (I), and the compound of formula (I) is reacted withtrimethylsulfoxonium chloride to form a compound of formula (II).Contacting the compound of formula (II) with an anhydrous source of HBror HCl yields the corresponding halomethyl ketone (III). Reaction of acompound of formula (III) with a compound of formula (IV) in thepresence of a base yields a compound of formula (V).

wherein PG, Ts, R₁, and X are as defined above.

The protecting group may be any suitable protecting group, such asdescribed herein. In one embodiment, the protecting group iscarboxybenzyl, and the compound of formula (XIa), (I), (II), (III),(IV), and (V) is compound (XI), (XII), (IIa), (IIIa), (IVa), and (Va),respectively. In one embodiment, the protecting group is carboxybenzyl,and X is Br. In one embodiment, R₁ is —OR₂ and R₂ is methyl or ethyl. Insuch embodiments, the compound of formula (IV) is a compound of formula(IVa).

In step (a) of Scheme XIII, the compound of formula (XIa) may becontacted with a catalyst, such as a ruthenium catalyst. Any catalystcomprising a chiral phosphine may be used. One particular example of asuitable catalyst isdiacetato[(S)-(−)5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole]ruthenium(II)(i.e., (S)-Segphos Ru(OAc)₂). Suitable solvents for use in step (a)include, but are not limited to, methanol, triethylamine, andcombinations thereof. In one embodiment, the reaction of step (a) ofScheme XIII is conducted under the conditions described above for step(a) of Scheme III.

The reaction in step (b) of Scheme XIII is generally accomplished in thepresence of a coupling agent, such as carbonyldiimidazole (CDI), and astrong base. The strong base may be, for example, potassiumtert-butoxide, sodium tert-butoxide, or combinations thereof. The step(b) reaction may be conducted in any suitable solvent including, but notlimited to, tetrahydrofuran, water, and methyl tert-butyl ether. In oneembodiment, the reaction is conducted in the presence ofcarbonyldiimidazole and potassium tert-butoxide. In one embodiment, thereaction of step (b) of Scheme XIII is conducted under the conditionsdescribed above for step (b) of Scheme III.

In step (c) of Scheme XIII, the compound of formula (II) is contactedwith an anhydrous source of HBr or HCl to form the compound of formula(III). The reaction may be conducted in any suitable solvent including,but not limited to, tetrahydrofuran, ethyl acetate, acetic acid,N,N-dimethylacetamide, heptanes, and combinations thereof. In oneembodiment, the reaction of step (c) of Scheme XIII is conducted underthe conditions described above for step (c) of Scheme III.

In step (d) of Scheme XIII, the compound of formula (III) is reactedwith a compound of formula (IV) or (IVa) (prepared as described herein).The step (d) reaction is conducted in the presence of a base, such aslithium tert-butoxide, sodium tert-butoxide, or combinations thereof. Inone embodiment, the base is lithium tert-butoxide. The reaction of step(d) may be conducted in any suitable solvent including, but not limitedto dimethylacetamide, tetrahydrofuran, dichloromethane, ethyl acetate,heptanes, and combinations thereof. In one embodiment, the reaction ofstep (d) of Scheme XIII is conducted under the conditions describedabove for step (d) of Scheme III.

As discussed herein, it has surprisingly been discovered that when R₁ is—OR₂, and R₂ is ethyl or methyl, the compound of formula (V) andsubsequent downstream compounds can be isolated as crystalline solids,which aids in purification of these intermediates. Thus, in anotheraspect, the present disclosure is directed to a process for preparing acrystalline compound of formula (V). The process comprises a) reacting acompound of formula (III):

with a compound of formula (IV):

to produce the compound of formula (V); wherein: PG is a protectinggroup; X is Br or Cl; R₁ is —OR₂; R₂ is methyl or ethyl; and Ts istosyl. In one embodiment, the process is conducted under the conditionsset forth above for step c) in Scheme XII or step (d) in Scheme XIII.

Formula (VII)

In another embodiment, the present disclosure is directed to compound(VII):

or a pharmaceutically acceptable salt thereof.

In one embodiment, the pharmaceutically acceptable salt of (VII) isselected from the group consisting of (VIIa), (VIIb), and (VIIc):

In some embodiments, any of the processes for preparing(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamidethat are disclosed herein may further comprise forming one of the solidstate forms described herein in Section III.

III. SOLID STATE FORMS

The present disclosure also relates to solid state forms of Compound 1.As with all pharmaceutical compounds and compositions, the chemical andphysical properties of Compound 1 are important in its commercialdevelopment. These properties include, but are not limited to: (1)packing properties such as molar volume, bulk density andhygroscopicity, (2) thermodynamic properties such as meltingtemperature, vapor pressure and solubility, (3) kinetic properties suchas dissolution rate and stability (including stability at ambientconditions, especially to moisture and under storage conditions), (4)surface properties such as surface area, wettability, interfacialtension and shape, (5) mechanical properties such as hardness, tensilestrength, compactibility, handling, flow and blend; and (6) filtrationproperties. These properties can affect, for example, the processing andstorage of the compound and pharmaceutical compositions comprising thecompound.

Solid state forms of Compound 1 that improve upon one or more of theseproperties relative to other solid state forms of the compound aredesirable. Isolating pharmaceutically acceptable solid state forms ofthe compound that can be manufactured and formulated on acommercial-scale has been a challenge.

The Amorphous Freebase form of Compound 1 generally has greatersolubility, and increased bioavailability relative to most of thecorresponding crystalline forms of the compound. The Amorphous Freebasealso has acceptable chemical stability. However, it is hygroscopic, andenvironmental controls potentially are required to ensure appropriatecontrol of potency and water content during storage, dispensing, andhandling of the Amorphous Freebase. In addition, the Amorphous Freebaseexhibits an oiling-out limit close to the solubility curve duringmanufacturing.

Crystalline Hydrochloride Solvate Form AA, crystalline HydrochlorideSolvate Form BB, and crystalline Hydrochloride Solvate Form CC generallyconvert to an amorphous hydrochloride upon ambient drying. The resultingamorphous hydrochloride is hygroscopic. Yields obtained for each of thecrystalline hydrochlorides generally have been low. HydrochlorideSolvate Form AA, Hydrochloride Solvate Form BB, and HydrochlorideSolvate form CC may not be suitable for large scale manufacturing.

The crystalline L-Maleate forms generally may be less chemically stablethan the Amorphous Freebase, the Freebase Hydrate Form C, and theTartrate Hydrate, and may not exhibit pharmaceutically acceptablestability for use as an active ingredient in a pharmaceutical dosageform.

The Tartrate Hydrate form has acceptable chemical stability, highsolubility, generally good impurity rejection during isolation and isnot hygroscopic. However, the Tartrate Hydrate presented challengesbecause of lack of physical stability which also impacted manufacturing.The Tartrate Hydrate dehydrated into Amorphous at low relative humidityand high temperature, e.g., <10% RH at 25° C. Shearing and compressionpotentially cause conversion to the amorphous tartrate, and therefore itis not suitable for compressing into tablet form. Additionally, thefilter cake solidified during drying, resulting in the need foradditional controls during drying.

Freebase Hydrate Form B has been manufactured on a large scale withoutthe need for labor-intensive and expensive techniques such asspray-drying. It also provided for appropriate control of the bulkproperties of the Amorphous Freebase. However, the Amorphous Freebaseexhibited poor impurity rejection when isolated via Freebase HydrateForm B, and required a dry environment for storage and control ofrelative humidity during manufacturing and packaging.

The Freebase Hydrate Form B was not physically stable. It desolvated (ordehydrated) and converted to the Amorphous Freebase upon drying.Although the Freebase Hydrate Form B generally did not exhibitpharmaceutically acceptable physical stability for use as an activeingredient in a pharmaceutical dosage form, it may be a usefulintermediate in the preparation of other solid state forms such as theAmorphous Freebase.

After years of experimentation, Freebase Hydrate Form C wasserendipitously discovered when attempting to scale up the AmorphousFreebase. It offers many surprising and superior properties over theAmorphous Freebase, the Tartrate Hydrate and other forms of Compound 1.

Freebase Hydrate Form C generally exhibits excellent chemical stability,physical stability, and solid state properties, including lowhygroscopicity and prismatic morphology. Freebase Hydrate Form C hasimproved bulk properties such as powder flow, bulk density, which arebeneficial in the formulation process. In addition, Freebase HydrateForm C offers at least the following unexpected advantages over theother forms: 1) efficient purification is obtained since there is noneed to use the tartrate crystal; 2) the seeding step is straightforwardsince Freebase Hydrate Form C can be stored at normal conditions; 3) thedrying step can be carried out at normal conditions with standardequipment since no dehydration occurs up to around 110° C.; 4) FreebaseHydrate Form C can be crystallized in different particle sizes.Large-scale manufacture of the Freebase Hydrate Form C is relativelystraightforward with minimal scaling, good yield, good impurityrejection, fast filtration, conventional drying, and minimal millingissues. In addition, Freebase Hydrate Form C can be grown into differentparticle sizes.

Freebase Anhydrate Form D can be manufactured only when the watercontent of the crystallization solvent is low, and will convert toFreebase Hydrate Form C in solutions at high water content. Themanufacture of Freebase Anhydrate Form D thus requires strict control ofwater content. Freebase Anhydrate Form D is slow to crystallize, anddifficult to manufacture in higher yield. This anhydrate is reversiblyhygroscopic (up to 1.8% water at 90% RH at 25° C.), and is metastablerelative to Freebase Hydrate Form C at typical environmental conditions(e.g., above 2.4% RH at 23° C.) used during storage for downstreamprocessing. Freebase Hydrate Form C will convert to Freebase AnhydrateForm D in a solution of ethyl acetate with low water content.

The sections below discuss solid state forms that have been identifiedand selected properties of those solid state forms.

A. Amorphous Freebase

In one embodiment, the solid state form is amorphous Compound 1 (the“Amorphous Freebase”). In one aspect, the Amorphous Freebase comprisesless than about 13% by weight water. In another aspect, the AmorphousFreebase comprises less than about 12% by weight water. In anotheraspect, the Amorphous Freebase comprises less than about 10% by weightwater. In another aspect, the Amorphous Freebase comprises less thanabout 9% by weight water. In another aspect, the Amorphous Freebasecomprises less than about 8% by weight water. In another aspect, theAmorphous Freebase comprises less than about 7% by weight water. Inanother aspect, the Amorphous Freebase comprises less than about 6% byweight water. In another aspect, the Amorphous Freebase comprises lessthan about 5% by weight water. In another aspect, the Amorphous Freebasecomprises less than about 4% by weight water. In another aspect, theAmorphous Freebase comprises less than about 3% by weight water. Inanother aspect, the Amorphous Freebase comprises less than about 2% byweight water. In another aspect, the Amorphous Freebase comprises lessthan about 1% by weight water. In another aspect, the Amorphous Freebasehas a glass transition temperature onset at about 119° C. In anotheraspect, the Amorphous Freebase has a glass transition temperaturemidpoint at about 122° C. In another aspect, the Amorphous Freebase hasa glass transition temperature onset at about 119° C. and a glasstransition temperature midpoint at about 122° C. The Amorphous Freebaseis further described in the Examples of the application.

The Amorphous Freebase generally has greater solubility, and increasedbioavailability, relative to the corresponding crystalline forms of thecompound. The Amorphous Freebase also has acceptable chemical stability.For example, when chemical stability was evaluated in closed vials at30° C./65% relative humidity and 40° C./75% relative humidity over 12weeks, and at 50° C./75% relative humidity over 6 weeks, no degradationof the Amorphous Freebase was observed in the closed vials under any ofthose conditions. In addition, the Amorphous Freebase exhibitsacceptable stability to light and peroxide. The Amorphous Freebase,however, is hygroscopic and can comprise as much as 12% by weight waterat 25° C./90% relative humidity. Environmental controls potentially arerequired to ensure appropriate control of potency and water contentduring storage, dispensing, and handling of the Amorphous Freebase.

The Amorphous Freebase can be prepared, for example, using anti-solventcrystallization to prepare the Freebase Solvate Form A or FreebaseHydrate Form B (described below) followed by dehydration or desolvationto yield the Amorphous Freebase. Thiscrystallization/dehydration/desolvation method allows for thelarge-scale manufacture of the Amorphous Freebase without the need forlabor-intensive and expensive techniques such as spray-drying. It alsoprovides for appropriate control of the bulk properties of the AmorphousFreebase (i.e., particle size, flow properties etc.). When the AmorphousFreebase is prepared by desolvation of the Freebase Solvate Form A ordehydration of the Freebase Hydrate Form B, the Amorphous Freebasegenerally retains the morphology of the Freebase Solvate Form A orFreebase Hydrate Form B (i.e., blades with hexagonal crystal faces whenprepared by dehydration of Freebase Hydrate Form B, or irregular whendesolvated from Freebase Solvate Form A).

The process volumes required for crystallization during the large-scalemanufacture of the Freebase Solvate Form A or Freebase Hydrate Form Bgenerally are within conventional processing volumes, but impurityrejection potentially may be lower than desired. Drying anddehydration/desolvation of the Freebase Hydrate Form B/Freebase SolvateForm A to the Amorphous Freebase generally can be carried out withstandard equipment under conventional conditions and the isolatedAmorphous Freebase typically can be co-milled without adverselyimpacting the amorphous state.

B. Crystalline Freebase Solvates and Hydrates

In another embodiment, the solid state form is a crystalline freebase ofCompound 1. In one aspect, the crystalline freebase is a solvate. Inanother aspect, the crystalline freebase is an isopropyl acetate/watersolvate (the “Freebase Solvate Form A”). In another aspect, thecrystalline freebase is a hydrate (the “Freebase Hydrate Form B”). TheFreebase Solvate Form A and the Freebase Hydrate Form B are furtherdescribed in the Examples of the application.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, and 12.0±0.2 degrees two theta when measured at about 25° C.with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, and 12.0±0.2 degrees two theta, and that is furthercharacterized by a peak at one or more of 13.7±0.2, 20.8±0.2 and25.0±0.2 degrees two theta when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, 12.0±0.2, and 20.8±0.2 degrees two theta, when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, 12.0±0.2, and 25.0±0.2 degrees two theta, when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, 12.0±0.2, 20.8±0.2, and 25.0±0.2 degrees two theta, whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, 12.0±0.2, 13.7±0.2, 20.8±0.2, and 25.0±0.2 degrees two thetawhen measured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern without a significant peak at one ormore of 15.1±0.2, and 21.7±0.2 degrees two theta when measured at about25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern without a significant peak at one ormore of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees two theta when measuredat about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern without a significant peak at one ormore of 15.1±0.2, and 21.7±0.2 degrees two theta, and without asignificant peak at one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, and 12.0±0.2 degrees two theta, and without a significant peakat one or more of 15.1±0.2, and 21.7±0.2 degrees two theta, whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, and 12.0±0.2 degrees two theta, and without a significant peakat one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees two theta, whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, and 12.0±0.2 degrees two theta, and without a significant peakat one or more of 15.1±0.2, and 21.7±0.2 degrees two theta, and withouta significant peak at one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, and 12.0±0.2, 13.7±0.2, 20.8±0.2, and 25.0±0.2 degrees twotheta, and without a significant peak at one or more of 15.1±0.2, and21.7±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, and 12.0±0.2, 13.7±0.2, 20.8±0.2, and 25.0±0.2 degrees twotheta, and without a significant peak at one or more of 3.9±0.2,6.8±0.2, and 14.1±0.2 degrees two theta, when measured at about 25° C.with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, and 12.0±0.2, 13.7±0.2, 20.8±0.2, and 25.0±0.2 degrees twotheta, and without a significant peak at one or more of 15.1±0.2, and21.7±0.2 degrees two theta, and without a significant peak at one ormore of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees two theta, when measuredat about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks substantially atthe positions listed in Table 16-A±0.2 degrees two theta, when measuredat about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks substantially atthe positions listed in Table 16-B±0.2 degrees two theta, when measuredat about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks substantially atthe positions listed in Table 16-B±0.2 degrees two theta that have arelative intensity of at least 10.0%, when measured at about 25° C. withmonochromatic Kα1 radiation.

In further aspects of each of the above embodiments, the significantpeak values have a variation of ±0.1 degrees two theta rather than ±0.2degrees two theta. In still further aspects of each of the aboveembodiments, the significant peak values have a variation of ±0.05degrees two theta rather than ±0.2 degrees two theta.

In one embodiment, the crystalline freebase has an X-ray powderdiffraction pattern substantially as shown in FIG. 3B.

In one embodiment, the crystalline freebase has a thermogravimetricanalysis profile showing a weight loss of about 5% to about 6% betweenabout 100° C. and about 160° C. when heated at a rate of 10° C./minute.

In one embodiment, the crystalline freebase has a thermogravimetricanalysis profile substantially as shown in FIG. 4D.

In one embodiment, the crystalline freebase has a differential scanningcalorimetry profile comprising a first endotherm between about 25° C. toabout 100° C. when heated at a rate of 10° C./minute.

In one embodiment, the crystalline freebase has a differential scanningcalorimetry profile comprising a first endotherm between about 59.90° C.to about 98.79° C. when heated at a rate of 10° C./minute.

In one embodiment, the crystalline freebase has a differential scanningcalorimetry profile comprising a second endotherm between about 100° C.to about 160° C. when heated at a rate of 10° C./minute.

In one embodiment, the crystalline freebase has a differential scanningcalorimetry profile comprising a second endotherm between about 109.31°C. to about 132.94° C. when heated at a rate of 10° C./minute.

In one embodiment, the crystalline freebase has a differential scanningcalorimetry profile comprising a first endotherm between about 25° C. toabout 100° C., and a second endotherm between about 100° C. to about160° C., when heated at a rate of 10° C./minute.

In one embodiment, the crystalline freebase has a differential scanningcalorimetry profile substantially as shown in FIG. 5B.

In one embodiment, the crystalline freebase has a thermogravimetricanalysis profile showing a weight loss of about 5% to about 6% betweenabout 100° C. and about 160° C. when heated at a rate of 10° C./minute;and a differential scanning calorimetry profile comprising a firstendotherm between about 25° C. to about 100° C. and/or a secondendotherm between about 100° C. to about 160° C., when heated at a rateof 10° C./minute. In one aspect, the differential scanning calorimetryprofile comprises a first endotherm between about 25° C. to about 100°C. when heated at a rate of 10° C./minute. In another aspect, thedifferential scanning calorimetry profile comprises a second endothermbetween about 100° C. to about 160° C. when heated at a rate of 10°C./minute. In another aspect, the differential scanning calorimetryprofile comprises a first endotherm between about 25° C. to about 100°C., and a second endotherm between about 100° C. to about 160° C., whenheated at a rate of 10° C./minute.

In one embodiment, the crystalline freebase has a thermogravimetricanalysis profile showing a weight loss of about 5% to about 6% betweenabout 100° C. and about 160° C. when heated at a rate of 10° C./minute;and a differential scanning calorimetry profile comprising a firstendotherm between about 59.90° C. to about 98.79° C. and/or a secondendotherm between about 109.31° C. to about 132.94° C., when heated at arate of 10° C./minute. In one aspect, the differential scanningcalorimetry profile comprises a first endotherm between about 59.90° C.to about 98.79° C. when heated at a rate of 10° C./minute. In anotheraspect, the differential scanning calorimetry profile comprises a secondendotherm between about 109.31° C. to about 132.94° C. when heated at arate of 10° C./minute. In another aspect, the differential scanningcalorimetry profile comprises a first endotherm between about 59.90° C.to about 98.79° C., and a second endotherm between about 109.31° C. toabout 132.94° C., when heated at a rate of 10° C./minute.

In one embodiment, the crystalline freebase has an X-ray diffractionpattern as previously described above, and further has at least one ofthe following: (a) a thermogravimetric analysis profile showing a weightloss of about 5% to about 6% between about 100° C. and about 160° C.when heated at a rate of 10° C./minute; and (b) a differential scanningcalorimetry profile comprising a first endotherm between about 25° C. toabout 100° C., and/or a second endotherm between about 100° C. to about160° C., when heated at a rate of 10° C./minute. In one aspect, thedifferential scanning calorimetry profile comprises a first endothermbetween about 25° C. to about 100° C. when heated at a rate of 10°C./minute. In another aspect, the differential scanning calorimetryprofile comprises a second endotherm between about 100° C. to about 160°C. when heated at a rate of 10° C./minute. In another aspect, thedifferential scanning calorimetry profile comprises a first endothermbetween about 25° C. to about 100° C., and a second endotherm betweenabout 100° C. to about 160° C., when heated at a rate of 10° C./minute.

In one embodiment, the crystalline freebase has an X-ray diffractionpattern as previously described above, and further has athermogravimetric analysis profile showing a weight loss of about 5% toabout 6% between about 100° C. and about 160° C. when heated at a rateof 10° C./minute.

In one embodiment, the crystalline freebase has an X-ray diffractionpattern as previously described above, and further has a differentialscanning calorimetry profile comprising a first endotherm between about25° C. to about 100° C., and/or a second endotherm between about 100° C.to about 160° C., when heated at a rate of 10° C./minute. In one aspect,the differential scanning calorimetry profile comprises a firstendotherm between about 25° C. to about 100° C. when heated at a rate of10° C./minute. In another aspect, the differential scanning calorimetryprofile comprises a second endotherm between about 100° C. to about 160°C. when heated at a rate of 10° C./minute. In another aspect, thedifferential scanning calorimetry profile comprises a first endothermbetween about 25° C. to about 100° C., and a second endotherm betweenabout 100° C. to about 160° C., when heated at a rate of 10° C./minute.

In one embodiment, the crystalline freebase has an X-ray diffractionpattern as previously described above; a thermogravimetric analysisprofile showing a weight loss of about 5% to about 6% between about 100°C. and about 160° C. when heated at a rate of 10° C./minute; and adifferential scanning calorimetry profile comprising a first endothermbetween about 25° C. to about 100° C., and/or a second endotherm betweenabout 100° C. to about 160° C., when heated at a rate of 10° C./minute.In one aspect, the differential scanning calorimetry profile comprises afirst endotherm between about 25° C. to about 100° C. when heated at arate of 10° C./minute. In another aspect, the differential scanningcalorimetry profile comprises a second endotherm between about 100° C.to about 160° C. when heated at a rate of 10° C./minute. In anotheraspect, the differential scanning calorimetry profile comprises a firstendotherm between about 25° C. to about 100° C., and a second endothermbetween about 100° C. to about 160° C., when heated at a rate of 10°C./minute.

The Freebase Solvate Form A and Freebase Hydrate Form B are notphysically stable. As discussed above, they desolvate (or dehydrate) andconvert to the Amorphous Freebase upon drying. Although the FreebaseSolvate Form A and Freebase Hydrate Form B generally do not exhibitpharmaceutically acceptable physical stability for use as an activeingredient in a pharmaceutical dosage form, they are usefulintermediates in the preparation of other solid state forms such as theAmorphous Freebase.

C. Crystalline Freebase Hydrate Form C (Hemihydrate)

In another embodiment, the solid state form is a crystalline hydrate,wherein the crystalline hydrate is a hemihydrate. In another embodiment,the solid state form is crystalline hemihydrate of Compound 1 having apowder X-ray diffraction pattern corresponding to Freebase Hydrate FormC. The Freebase Hydrate Form C is further described in the Examples ofthe application.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and21.7±0.2 degrees two theta when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and21.7±0.2 degrees two theta, and that is further characterized by a peakat one or more of 7.7±0.2, 7.9±0.2, 9.6±0.2, 10.3±0.2, 13.9±0.2,15.5±0.2, 15.9±0.2, 17.0±0.2, 17.2±0.2, 17.8±0.2, 18.1±0.2, 18.3±0.2,19.3±0.2, 19.7±0.2, 20.5±0.2, 20.9±0.2, 21.9±0.2, 22.2±0.2, 23.5±0.2,24.4±0.2, 24.9±0.2, 28.2±0.2, and 29.5±0.2 degrees two theta whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern that is characterized by peaks at 13.4±0.2,15.1±0.2, 15.5±0.2, and 21.7±0.2 degrees two theta when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern that is characterized by peaks at 13.4±0.2,15.1±0.2, 17.0±0.2, and 21.7±0.2 degrees two theta when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern that is characterized by peaks at 13.4±0.2,15.1±0.2, 20.9±0.2, and 21.7±0.2 degrees two theta when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern that is characterized by peaks at 13.4±0.2,15.1±0.2, 15.5±0.2, 17.0±0.2, 20.9±0.2, and 21.7±0.2 degrees two thetawhen measured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 15.5±0.2, 13.4±0.2,15.1±0.2, 19.3±0.2, 20.5±0.2, and 21.7±0.2 degrees two theta whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern without a significant peak at one or more of3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta, when measured at about25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern without a significant peak at one or more of3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees two theta, when measured at about25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern without a significant peak at one or more of3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta, and without asignificant peak at one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and21.7±0.2 degrees two theta, and without a significant peak at one ormore of 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta, when measuredat about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and21.7±0.2 degrees two theta, and without a significant peak at one ormore of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees two theta, when measuredat about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and21.7±0.2 degrees two theta, and without a significant peak at one ormore of 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta, and without asignificant peak at one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 15.5±0.2, 13.4±0.2,15.1±0.2, 19.3±0.2, 20.5±0.2, and 21.7±0.2 degrees two theta, andwithout a significant peak at one or more of 3.1±0.2, 9.3±0.2, and12.0±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 15.5±0.2, 13.4±0.2,15.1±0.2, 19.3±0.2, 20.5±0.2, and 21.7±0.2 degrees two theta, andwithout a significant peak at one or more of 3.9±0.2, 6.8±0.2, and14.1±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 15.5±0.2, 13.4±0.2,15.1±0.2, 19.3±0.2, 20.5±0.2, and 21.7±0.2 degrees two theta, andwithout a significant peak at one or more of 3.1±0.2, 9.3±0.2, and12.0±0.2 degrees two theta, and without a significant peak at one ormore of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees two theta, when measuredat about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks substantially at thepositions listed in Table 16-C±0.2 degrees two theta, when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks substantially at thepositions listed in Table 16-C±0.2 degrees two theta that have arelative intensity of at least 10.0%, when measured at about 25° C. withmonochromatic Kα1 radiation.

In further aspects of each of the above embodiments, the significantpeak values have a variation of ±0.1 degrees two theta rather than ±0.2degrees two theta. In still further aspects of each of the aboveembodiments, the significant peak values have a variation of ±0.05degrees two theta rather than ±0.2 degrees two theta.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern substantially as shown in FIG. 3C when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has a thermogravimetricanalysis profile showing a weight loss of about 2.3% to about 2.6%between about 120° C. and 160° C. when heated at a rate of 10°C./minute.

In one embodiment, the Freebase Hydrate Form C has a thermogravimetricanalysis profile showing a weight loss of about 2.3% to about 2.6%between about 114.52° C. and 168.15° C. when heated at a rate of 10°C./minute.

In one embodiment, the Freebase Hydrate Form C has a thermogravimetricanalysis profile substantially as shown in FIG. 4E.

In one embodiment, the Freebase Hydrate Form C has a differentialscanning calorimetry profile comprising an endotherm between about 120°C. and about 170° C. when heated at a rate of 10° C./minute.

In one embodiment, the Freebase Hydrate Form C has a differentialscanning calorimetry profile comprising an endotherm between about134.70° C. and about 167.53° C. when heated at a rate of 10° C./minute.

In one embodiment, the Freebase Hydrate Form C has a differentialscanning calorimetry profile substantially as shown in FIG. 5C.

In one embodiment, the Freebase Hydrate Form C has a moisture sorptionisotherm profile showing a weight gain of about 0% to about 0.2% whenrelative humidity is increased from about 0% relative humidity to about90% relative humidity at a temperature of 25° C.

In one embodiment, the Freebase Hydrate Form C has a moisture sorptionisotherm profile substantially as shown in FIG. 6B.

In one embodiment, the Freebase Hydrate Form C has a thermogravimetricanalysis profile showing a weight loss of about 2.3% to about 2.6%between about 120° C. and 160° C. when heated at a rate of 10°C./minute; and a differential scanning calorimetry profile comprising anendotherm between about 120 and about 170° C. when heated at a rate of10° C./minute.

In one embodiment, the Freebase Hydrate Form C has a thermogravimetricanalysis profile showing a weight loss of about 2.3% to about 2.6%between about 120° C. and 160° C. when heated at a rate of 10°C./minute; and a moisture sorption isotherm profile showing a weightgain of about 0% to about 0.2% when relative humidity is increased fromabout 0% relative humidity to about 90% relative humidity at atemperature of 25° C.

In one embodiment, the Freebase Hydrate Form C has a differentialscanning calorimetry profile comprising an endotherm between about 120and about 170° C. when heated at a rate of 10° C./minute; and a moisturesorption isotherm profile showing a weight gain of about 0% to about0.2% when relative humidity is increased from about 0% relative humidityto about 90% relative humidity at a temperature of 25° C.

In one embodiment, the Freebase Hydrate Form C has a thermogravimetricanalysis profile showing a weight loss of about 2.3% to about 2.6%between about 120° C. and 160° C. when heated at a rate of 10°C./minute; a differential scanning calorimetry profile comprising anendotherm between about 120 and about 170° C. when heated at a rate of10° C./minute; and a moisture sorption isotherm profile showing a weightgain of about 0% to about 0.2% when relative humidity is increased fromabout 0% relative humidity to about 90% relative humidity at atemperature of 25° C.

In one embodiment, the Freebase Hydrate Form C has a thermogravimetricanalysis profile showing a weight loss of about 2.3% to about 2.6%between about 120° C. and 160° C. when heated at a rate of 10°C./minute; a differential scanning calorimetry profile comprising anendotherm between about 134.70 and about 167.53° C. when heated at arate of 10° C./minute; and a moisture sorption isotherm profile showinga weight gain of about 0% to about 0.2% when relative humidity isincreased from about 0% relative humidity to about 90% relative humidityat a temperature of 25° C.

In one embodiment, the Freebase Hydrate Form C has an orthorhombiclattice type.

In one embodiment, the Freebase Hydrate Form C has a P212121 spacegroup.

In one embodiment, the Freebase Hydrate Form C has unit cell a, b and cvalues of about 12.7 Å, about 13.1 Å, and about 22.6 Å, respectively.

In one embodiment, the Freebase Hydrate Form C has an X-ray diffractionpattern as previously described above, and at least one of thefollowing: (a) a thermogravimetric analysis profile showing a weightloss of about 2.3% to about 2.6% between about 120° C. and 160° C. whenheated at a rate of 10° C./minute; (b) a differential scanningcalorimetry profile comprising an endotherm between about 120 and about170° C. when heated at a rate of 10° C./minute; and/or (c) a moisturesorption isotherm profile showing a weight gain of about 0% to about0.2% when relative humidity is increased from about 0% relative humidityto about 90% relative humidity at a temperature of 25° C.

In one embodiment, the Freebase Hydrate Form C has an X-ray diffractionpattern as previously described above, and a thermogravimetric analysisprofile showing a weight loss of about 2.3% to about 2.6% between about120° C. and 160° C. when heated at a rate of 10° C./minute.

In one embodiment, the Freebase Hydrate Form C has an X-ray diffractionpattern as previously described above, and a differential scanningcalorimetry profile comprising an endotherm between about 120 and about170° C. when heated at a rate of 10° C./minute.

In one embodiment, the Freebase Hydrate Form C has an X-ray diffractionpattern as previously described above, and a moisture sorption isothermprofile showing a weight gain of about 0% to about 0.2% when relativehumidity is increased from about 0% relative humidity to about 90%relative humidity at a temperature of 25° C.

In one embodiment, the Freebase Hydrate Form C has an X-ray diffractionpattern as previously described above; a thermogravimetric analysisprofile showing a weight loss of about 2.3% to about 2.6% between about120° C. and 160° C. when heated at a rate of 10° C./minute; and adifferential scanning calorimetry profile comprising an endothermbetween about 120 and about 170° C. when heated at a rate of 10°C./minute.

In one embodiment, the Freebase Hydrate Form C has an X-ray diffractionpattern as previously described above; a thermogravimetric analysisprofile showing a weight loss of about 2.3% to about 2.6% between about120° C. and 160° C. when heated at a rate of 10° C./minute; and amoisture sorption isotherm profile showing a weight gain of about 0% toabout 0.2% when relative humidity is increased from about 0% relativehumidity to about 90% relative humidity at a temperature of 25° C.

In one embodiment, the Freebase Hydrate Form C has an X-ray diffractionpattern as previously described above; a differential scanningcalorimetry profile comprising an endotherm between about 120 and about170° C. when heated at a rate of 10° C./minute; and a moisture sorptionisotherm profile showing a weight gain of about 0% to about 0.2% whenrelative humidity is increased from about 0% relative humidity to about90% relative humidity at a temperature of 25° C.

In one embodiment, the Freebase Hydrate Form C has an X-ray diffractionpattern as previously described above; a thermogravimetric analysisprofile showing a weight loss of about 2.3% to about 2.6% between about120° C. and 160° C. when heated at a rate of 10° C./minute; adifferential scanning calorimetry profile comprising an endothermbetween about 120 and about 170° C. when heated at a rate of 10°C./minute; and a moisture sorption isotherm profile showing a weightgain of about 0% to about 0.2% when relative humidity is increased fromabout 0% relative humidity to about 90% relative humidity at atemperature of 25° C.

The Freebase Hydrate Form C generally exhibits good chemical stability,physical stability, and solid state properties (including lowhygroscopicity). Large-scale manufacture of the Freebase Hydrate Form Cis relatively straightforward with minimal scaling, good yield, goodimpurity rejection, fast filtration, conventional drying, and minimalmilling issues (even after subjecting the isolated material to highenergy pinmilling). In addition, different particle sizes can beachieved through appropriate control of the crystallization process.

D. Crystalline Freebase Anhydrate Form D

In another embodiment, the solid state form is a crystalline anhydratefreebase of Compound 1 having a powder X-ray diffraction patterncorresponding to Freebase Anhydrate Form D. The Freebase Anhydrate FormD is further described in the Examples of the application.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta, and that is furthercharacterized by a peak at one or more of 4.0±0.2, 18.4±0.2, 19.0±0.2,23.0±0.2, and 24.7±0.2 degrees two theta, when measured at about 25° C.with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta, when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 18.4±0.2 and 20.3±0.2 degrees two theta, whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 19.0±0.2 and 20.3±0.2 degrees two theta, whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 19.0±0.2 and 20.3±0.2 degrees two theta, whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 20.3±0.2, and 23.0±0.2 degrees two theta, whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 20.3±0.2, and 24.7±0.2 degrees two theta, whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 4.0±0.2, 14.5±0.2, and19.0±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 4.0±0.2, 14.5±0.2, and19.0±0.2 degrees two theta, and that is further characterized by a peakat one or more of 8.0±0.2, 9.7±0.2, 14.2±0.2, 18.4±0.2, 20.3±0.2,23.0±0.2, and 24.7±0.2 degrees two theta, when measured at about 25° C.with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern without a significant peak at one or more of3.1±0.2, 9.3±0.2, and 20.8±0.2 degrees two theta, when measured at about25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern without a significant peak at one or more of6.8±0.2, 15.7±0.2, and 21.9±0.2 degrees two theta, when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern without a significant peak at one or more of13.4±0.2, 15.5±0.2, and 21.7±0.2 degrees two theta, when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern without a significant peak at one or more of13.4±0.2, 15.5±0.2, and 21.7±0.2 degrees two theta, and without asignificant peak at one or more of 6.8±0.2, 15.7±0.2, and 21.9±0.2degrees two theta, and without a significant peak at one or more of3.1±0.2, 9.3±0.2, and 20.8±0.2 degrees two theta, when measured at about25° C. with monochromatic Kα1 radiation.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta, and without asignificant peak at one or more of 3.1±0.2, 9.3±0.2, and 20.8±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta, and without asignificant peak at one or more of 6.8±0.2, 15.7±0.2, and 21.9±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta, and without asignificant peak at one or more of 13.4±0.2, 15.5±0.2, and 21.7±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta, and without asignificant peak at one or more of 3.1±0.2, 9.3±0.2, and 20.8±0.2degrees two theta, and without a significant peak at one or more of6.8±0.2, 15.7±0.2, and 21.9±0.2 degrees two theta, and without asignificant peak at one or more of 13.4±0.2, 15.5±0.2, and 21.7±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 19.0±0.2, and 20.3±0.2 degrees two theta, andwithout a significant peak at one or more of 3.1±0.2, 9.3±0.2, and20.8±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 19.0±0.2, and 20.3±0.2 degrees two theta, andwithout a significant peak at one or more of 6.8±0.2, 15.7±0.2, and21.9±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 19.0±0.2, and 20.3±0.2 degrees two theta, andwithout a significant peak at one or more of 13.4±0.2, 15.5±0.2, and21.7±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 19.0±0.2, and 20.3±0.2 degrees two theta, andwithout a significant peak at one or more of 3.1±0.2, 9.3±0.2, and20.8±0.2 degrees two theta, and without a significant peak at one ormore of 6.8±0.2, 15.7±0.2, and 21.9±0.2 degrees two theta, and without asignificant peak at one or more of 13.4±0.2, 15.5±0.2, and 21.7±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks substantially at thepositions listed in Table 16-J±0.2 degrees two theta, when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks substantially at thepositions listed in Table 16-J±0.2 degrees two theta that have arelative intensity of at least 10.0%, when measured at about 25° C. withmonochromatic Kα1 radiation.

In further aspects of each of the above embodiments, the significantpeak values have a variation of ±0.1 degrees two theta rather than ±0.2degrees two theta. In still further aspects of each of the aboveembodiments, the significant peak values have a variation of ±0.05degrees two theta rather than ±0.2 degrees two theta.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern substantially as shown in FIG. 3J when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has a thermogravimetricanalysis profile showing a weight loss of about 0.5% to about 0.8%between about 43° C. and 188° C. when heated at a rate of 10° C./minute.

In one embodiment, the Freebase Anhydrate Form D has a thermogravimetricanalysis profile showing a weight loss of about 0.5% to about 0.8%between about 41.36° C. and 190.48° C. when heated at a rate of 10°C./minute.

In one embodiment, the Freebase Anhydrate Form D has a thermogravimetricanalysis profile showing a weight loss of about 0.45% to about 0.55%between about 43° C. and 100° C. when heated at a rate of 10° C./minute.

In one embodiment, the Freebase Anhydrate Form D has a thermogravimetricanalysis profile showing a weight loss of about 0.5% between about 43°C. and 100° C. when heated at a rate of 10° C./minute.

In one embodiment, the Freebase Anhydrate Form D has a thermogravimetricanalysis profile substantially as shown in FIG. 4I

In one embodiment, the Freebase Anhydrate Form D has a differentialscanning calorimetry profile comprising an endotherm between about 180°C. and about 220° C. when heated at a rate of 10° C./minute.

In one embodiment, the Freebase Anhydrate Form D has a differentialscanning calorimetry profile comprising an endotherm between about199.55° C. and about 217.41° C. when heated at a rate of 10° C./minute.

In one embodiment, the Freebase Anhydrate Form D has a differentialscanning calorimetry profile comprising an endotherm with an onsetmelting point of about 199.55° C. and a melting enthalpy of about 85.4J/g.

In one embodiment, the Freebase Anhydrate Form D has a differentialscanning calorimetry profile substantially as shown in FIG. 5E.

In one embodiment, the Freebase Anhydrate Form D has a moisture sorptionisotherm profile showing a weight gain of about 1.6% to about 2.0% whenrelative humidity is increased from about 0% relative humidity to about90% relative humidity at a temperature of 25° C.

In one embodiment, the Freebase Anhydrate Form D has a moisture sorptionisotherm profile substantially as shown in FIG. 6D.

In one embodiment, the Freebase Anhydrate Form D has a thermogravimetricanalysis profile showing a weight loss of about 0.5% to about 0.8%between about 43° C. and 188° C. when heated at a rate of 10° C./minute;and a differential scanning calorimetry profile comprising an endothermbetween about 180° C. and about 220° C. when heated at a rate of 10°C./minute.

In one embodiment, the Freebase Anhydrate Form D has a thermogravimetricanalysis profile showing a weight loss of about 0.5% to about 0.8%between about 43° C. and 188° C. when heated at a rate of 10° C./minute;and a moisture sorption isotherm profile showing a weight gain of about1.6% to about 2.0% when relative humidity is increased from about 0%relative humidity to about 90% relative humidity at a temperature of 25°C.

In one embodiment, the Freebase Anhydrate Form D has a differentialscanning calorimetry profile comprising an endotherm between about 180°C. and about 220° C. when heated at a rate of 10° C./minute; and amoisture sorption isotherm profile showing a weight gain of about 1.6%to about 2.0% when relative humidity is increased from about 0% relativehumidity to about 90% relative humidity at a temperature of 25° C.

In one embodiment, the Freebase Anhydrate Form D has a thermogravimetricanalysis profile showing a weight loss of about 0.5% to about 0.8%between about 43° C. and 188° C. when heated at a rate of 10° C./minute;a differential scanning calorimetry profile comprising an endothermbetween about 180° C. and about 220° C. when heated at a rate of 10°C./minute; and a moisture sorption isotherm profile showing a weightgain of about 1.6% to about 2.0% when relative humidity is increasedfrom about 0% relative humidity to about 90% relative humidity at atemperature of 25° C.

In one embodiment, the Freebase Anhydrate Form D has a thermogravimetricanalysis profile showing a weight loss of about 0.5% to about 0.8%between about 43° C. and 188° C. when heated at a rate of 10° C./minute;a differential scanning calorimetry profile comprising an endothermbetween about 199.55° C. and about 217.41° C. when heated at a rate of10° C./minute; and a moisture sorption isotherm profile showing a weightgain of about 1.6% to about 2.0% when relative humidity is increasedfrom about 0% relative humidity to about 90% relative humidity at atemperature of 25° C.

In one embodiment, the Freebase Anhydrate Form D has an orthorhombiclattice type.

In one embodiment, the Freebase Anhydrate Form D has a P2₁2₁2 spacegroup.

In one embodiment, the Freebase Anhydrate Form D has unit cell a, b andc values of about 43.8 Å, about 8.6 Å, and about 9.2 Å, respectively.

In one embodiment, the Freebase Anhydrate Form D has an X-raydiffraction pattern as previously described above, and at least one ofthe following: (a) a thermogravimetric analysis profile showing a weightloss of about 0.5% to about 0.8% between about 43° C. and 188° C. whenheated at a rate of 10° C./minute; (b) a differential scanningcalorimetry profile comprising an endotherm between about 180° C. andabout 220° C. when heated at a rate of 10° C./minute; and/or (c) amoisture sorption isotherm profile showing a weight gain of about 1.6%to about 2.0% when relative humidity is increased from about 0% relativehumidity to about 90% relative humidity at a temperature of 25° C.

In one embodiment, the Freebase Anhydrate Form D has an X-raydiffraction pattern as previously described above, and athermogravimetric analysis profile showing a weight loss of about 0.5%to about 0.8% between about 43° C. and 188° C. when heated at a rate of10° C./minute.

In one embodiment, the Freebase Anhydrate Form D has an X-raydiffraction pattern as previously described above, and a differentialscanning calorimetry profile comprising an endotherm between about 180°C. and about 220° C. when heated at a rate of 10° C./minute.

In one embodiment, the Freebase Anhydrate Form D has an X-raydiffraction pattern as previously described above, and a moisturesorption isotherm profile showing a weight gain of about 1.6% to about2.0% when relative humidity is increased from about 0% relative humidityto about 90% relative humidity at a temperature of 25° C.

In one embodiment, the Freebase Anhydrate Form D has an X-raydiffraction pattern as previously described above; a thermogravimetricanalysis profile showing a weight loss of about 0.5% to about 0.8%between about 43° C. and 188° C. when heated at a rate of 10° C./minute;and a differential scanning calorimetry profile comprising an endothermbetween about 180° C. and about 220° C. when heated at a rate of 10°C./minute.

In one embodiment, the Freebase Anhydrate Form D has an X-raydiffraction pattern as previously described above; a thermogravimetricanalysis profile showing a weight loss of about 0.5% to about 0.8%between about 43° C. and 188° C. when heated at a rate of 10° C./minute;and a moisture sorption isotherm profile showing a weight gain of about1.6% to about 2.0% when relative humidity is increased from about 0%relative humidity to about 90% relative humidity at a temperature of 25°C.

In one embodiment, the Freebase Anhydrate Form D has an X-raydiffraction pattern as previously described above; a differentialscanning calorimetry profile comprising an endotherm between about 180°C. and about 220° C. when heated at a rate of 10° C./minute; and amoisture sorption isotherm profile showing a weight gain of about 1.6%to about 2.0% when relative humidity is increased from about 0% relativehumidity to about 90% relative humidity at a temperature of 25° C.

In one embodiment, the Freebase Anhydrate Form D has an X-raydiffraction pattern as previously described above; a thermogravimetricanalysis profile showing a weight loss of about 0.5% to about 0.8%between about 43° C. and 188° C. when heated at a rate of 10° C./minute;a differential scanning calorimetry profile comprising an endothermbetween about 180° C. and about 220° C. when heated at a rate of 10°C./minute; and a moisture sorption isotherm profile showing a weightgain of about 1.6% to about 2.0% when relative humidity is increasedfrom about 0% relative humidity to about 90% relative humidity at atemperature of 25° C.

Freebase Anhydrate Form D is reversibly hygroscopic (up to 1.8% water at90% RH at 25° C.), and is metastable relative to Freebase Hydrate Form Cat typical environmental conditions (e.g., above 2.4% RH at 23° C.) usedduring storage for downstream processing. The manufacture of FreebaseAnhydrate Form D requires strict control of water, as the FreebaseAnhydrate Form D can be manufactured only when the water content of thecrystallization solvent is low (e.g., less than 0.15% at 23° C.,corresponding to a water activity of 2.4%), and will convert to FreebaseHydrate Form C in solutions at high water content. Freebase AnhydrateForm D is slow to crystallize, and difficult to manufacture in higheryield.

E. Crystalline Tartrate

In another embodiment, the solid state form is a tartrate of Compound 1.In one aspect, the tartrate is amorphous. In another aspect, thetartrate is crystalline. In another aspect, the crystalline tartrate isa solvate. In another aspect, the crystalline tartrate is a hydrate. Inanother aspect, the tartrate is a crystalline L-tartrate. In anotheraspect, the crystalline L-tartrate is a hydrate. In another aspect, thecrystalline tartrate is a tetrahydrate (the “Tartrate Hydrate”). TheTartrate Hydrate (a tetrahydrate) is further described in the Examplesof the application.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern characterized by peaks at 3.9±0.2, 6.8±0.2, and 14.1±0.2 degreestwo theta when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern characterized by peaks at 3.9±0.2, 6.8±0.2, 14.1±0.2, 15.7±0.2,21.9±0.2, and 25.9±0.2 degrees two theta when measured at about 25° C.with monochromatic Kα1 radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern without a significant peak at one or more of 13.4±0.2 and15.1±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern without a significant peak at one or more of 3.1±0.2, 9.3±0.2,and 12.0±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern without a significant peak at one or more of 13.4±0.2 and15.1±0.2 degrees two theta, and without a significant peak at one ormore of 3.1±0.2 and 9.3±0.2 degrees two theta, when measured at about25° C. with monochromatic Kα1 radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern characterized by peaks at 3.9±0.2, 6.8±0.2, and 14.1±0.2 degreestwo theta, and without a significant peak at one or more of 13.4±0.2 and15.1±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern characterized by peaks at 3.9±0.2, 6.8±0.2, and 14.1±0.2 degreestwo theta, and without a significant peak at one or more of 3.1±0.2,9.3±0.2, and 12.0±0.2 degrees two theta, when measured at about 25° C.with monochromatic Kα1 radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern characterized by peaks at 3.9±0.2, 6.8±0.2, and 14.1±0.2 degreestwo theta, and without a significant peak at one or more of 13.4±0.2 and15.1±0.2 degrees two theta, and without a significant peak at one ormore of 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta, when measuredat about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern characterized by peaks at 3.9±0.2, 6.8±0.2, 14.1±0.2, 15.7±0.2,21.9±0.2 degrees two theta, and without a significant peak at one ormore of 13.4±0.2 and 15.1±0.2 degrees two theta, when measured at about25° C. with monochromatic Kα1 radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern characterized by peaks at 3.9±0.2, 6.8±0.2, 14.1±0.2, 15.7±0.2,21.9±0.2 degrees two theta, and without a significant peak at one ormore of 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern characterized by peaks at 3.9±0.2, 6.8±0.2, 14.1±0.2, 15.7±0.2,21.9±0.2 degrees two theta, and without a significant peak at one ormore of 13.4±0.2 and 15.1±0.2 degrees two theta, and without asignificant peak at one or more of 3.1±0.2, 9.3±0.2, and 12.0±0.2degrees two theta.

In further aspects of each of the above embodiments, the significantpeak values have a variation of ±0.1 degrees two theta rather than ±0.2degrees two theta. In still further aspects of each of the aboveembodiments, the significant peak values have a variation of ±0.05degrees two theta rather than ±0.2 degrees two theta.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern substantially as shown in FIG. 3D, when measured at about 25° C.with monochromatic Kα1 radiation.

In one embodiment, the Tartrate Hydrate has a thermogravimetric analysisprofile showing a weight loss of about 11.8% to about 12.2% betweenabout 25° C. and 160° C. when heated at a rate of 10° C./minute.

In one embodiment, the Tartrate Hydrate has a thermogravimetric analysisprofile showing a weight loss of about 11.8% to about 12.2% betweenabout 32.98° C. and 159.76° C. when heated at a rate of 10° C./minute.

In one embodiment, the Tartrate Hydrate has a thermogravimetric analysisprofile substantially as shown in FIG. 4F.

In one embodiment, the Tartrate Hydrate has a differential scanningcalorimetry profile comprising an endotherm between about 60° C. andabout 100° C. when heated at a rate of 10° C./minute.

In one embodiment, the Tartrate Hydrate has a differential scanningcalorimetry profile comprising an endotherm between about 75.74° C. andabout 110.26° C. when heated at a rate of 10° C./minute.

In one embodiment, the Tartrate Hydrate has a differential scanningcalorimetry profile substantially as shown in FIG. 5D.

In one embodiment, the Tartrate Hydrate has a thermogravimetric analysisprofile showing a weight loss of about 11.8% to about 12.2% betweenabout 25° C. and 160° C. when heated at a rate of 10° C./minute; and adifferential scanning calorimetry profile comprising an endothermbetween about 60° C. and about 100° C. when heated at a rate of 10°C./minute.

In one embodiment, the Tartrate Hydrate has a moisture sorption isothermprofile showing a weight gain of about 1% to about 2% when relativehumidity is increased from about 10% relative humidity to about 90%relative humidity at a temperature of 25° C.

In one embodiment, the Tartrate Hydrate has a moisture sorption isothermprofile substantially as shown in FIG. 6C.

In one embodiment, the Tartrate Hydrate has a thermogravimetric analysisprofile showing a weight loss of about 11.8% to about 12.2% betweenabout 25° C. and 160° C. when heated at a rate of 10° C./minute; adifferential scanning calorimetry profile comprising an endothermbetween about 60° C. and about 100° C. when heated at a rate of 10°C./minute; and a moisture sorption isotherm profile showing a weightgain of about 1% to about 2% when relative humidity is increased fromabout 10% relative humidity to about 90% relative humidity at atemperature of 25° C.

In one embodiment, the Tartrate Hydrate has an X-ray diffraction patternas previously described above, and at least one of the following: (a) athermogravimetric analysis profile showing a weight loss of about 11.8%to about 12.2% between about 25° C. and 160° C. when heated at a rate of10° C./minute; (b) a differential scanning calorimetry profilecomprising an endotherm between about 60° C. and about 100° C. whenheated at a rate of 10° C./minute; and/or (c) a moisture sorptionisotherm profile showing a weight gain of about 1% to about 2% whenrelative humidity is increased from about 10% relative humidity to about90% relative humidity at a temperature of 25° C.

In one embodiment, the Tartrate Hydrate has an X-ray diffraction patternas previously described above, and a thermogravimetric analysis profileshowing a weight loss of about 11.8% to about 12.2% between about 25° C.and 160° C. when heated at a rate of 10° C./minute.

In one embodiment, the Tartrate Hydrate has an X-ray diffraction patternas previously described above, and a differential scanning calorimetryprofile comprising an endotherm between about 60° C. and about 100° C.when heated at a rate of 10° C./minute.

In one embodiment, the Tartrate Hydrate has an X-ray diffraction patternas previously described above, and a moisture sorption isotherm profileshowing a weight gain of about 1% to about 2% when relative humidity isincreased from about 10% relative humidity to about 90% relativehumidity at a temperature of 25° C.

In one embodiment, the Tartrate Hydrate has an X-ray diffraction patternas previously described above; a thermogravimetric analysis profileshowing a weight loss of about 11.8% to about 12.2% between about 25° C.and 160° C. when heated at a rate of 10° C./minute; and a differentialscanning calorimetry profile comprising an endotherm between about 60°C. and about 100° C. when heated at a rate of 10° C./minute.

In one embodiment, the Tartrate Hydrate has an X-ray diffraction patternas previously described above; a thermogravimetric analysis profileshowing a weight loss of about 11.8% to about 12.2% between about 25° C.and 160° C. when heated at a rate of 10° C./minute; and a moisturesorption isotherm profile showing a weight gain of about 1% to about 2%when relative humidity is increased from about 10% relative humidity toabout 90% relative humidity at a temperature of 25° C.

In one embodiment, the Tartrate Hydrate has an X-ray diffraction patternas previously described above; a differential scanning calorimetryprofile comprising an endotherm between about 60° C. and about 100° C.when heated at a rate of 10° C./minute; and a moisture sorption isothermprofile showing a weight gain of about 1% to about 2% when relativehumidity is increased from about 10% relative humidity to about 90%relative humidity at a temperature of 25° C.

In one embodiment, the Tartrate Hydrate has an X-ray diffraction patternas previously described above; a thermogravimetric analysis profileshowing a weight loss of about 11.8% to about 12.2% between about 25° C.and 160° C. when heated at a rate of 10° C./minute; a differentialscanning calorimetry profile comprising an endotherm between about 60°C. and about 100° C. when heated at a rate of 10° C./minute; and amoisture sorption isotherm profile showing a weight gain of about 1% toabout 2% when relative humidity is increased from about 10% relativehumidity to about 90% relative humidity at a temperature of 25° C.

The Tartrate Hydrate has acceptable chemical stability and exhibitsacceptable stability to light and peroxide. For example, when chemicalstability was evaluated in closed vials at 30° C./65% relative humidityand 40° C./75% relative humidity over 12 weeks, and at 50° C./75%relative humidity over 6 weeks, no degradation of the Tartrate Hydratewas observed in the closed vials under any of the conditions. TheTartrate Hydrate has good solubility (BCS Class I) and is nothygroscopic. The Tartrate Hydrate, however, potentially will convert toan amorphous tartrate below 10% relative humidity, when heated, or whencompressed or under shear.

The Tartrate Hydrate can be manufactured, for example, usinganti-solvent crystallization. Impurity rejection during the large-scalemanufacture of the Tartrate Hydrate generally is good, but scaling maybe greater than desired and specific anti-solvent addition controls andprocess volume restrictions potentially may be required. In addition,appropriate control of the filtration, washing, and drying steps may berequired to minimize consolidation of the wet cake and formation of hardlumps in the isolated material. For example, control of the relativehumidity (e.g., greater than 10% and less than 100% relative humidity),temperature (e.g., crystallization at about 10° C. works well), andmixing rate may be required during drying to minimize the formation ofhard lumps in the isolated material. Insufficient control of the dryingconditions potentially will produce a consolidated, harder material thatmay be difficult to break up during subsequent processing. As previouslynoted, shearing and compression potentially will cause conversion to theamorphous tartrate. The dried material typically is milled withmechanical impact mills (e.g., Fitzmills and pin mills) becauseshear-based mills (e.g., comills) can lead to loss of crystallinity. Inaddition, loss of crystallinity potentially can result from pressure orcompression forces during formulation (such as would be required fortableting).

F. Crystalline Hydrochloride

In another embodiment, the solid state form is a crystallinehydrochloride of Compound 1. In one aspect, the crystallinehydrochloride corresponds to crystalline Hydrochloride Solvate Form AA.In another aspect, the crystalline hydrochloride corresponds tocrystalline Hydrochloride Solvate Form BB. In another aspect, thecrystalline hydrochloride corresponds to crystalline HydrochlorideSolvate Form CC. Hydrochloride Solvate Form AA, Hydrochloride SolvateForm BB, and Hydrochloride Solvate Form CC are further described in theExamples of the application.

Hydrochloride Solvate Form AA, Hydrochloride Solvate Form BB, andHydrochloride Solvate Form CC appear to be solvates and generallyconvert to an amorphous hydrochloride upon ambient drying. The resultingamorphous hydrochloride is hygroscopic. Yields obtained for each of thecrystalline hydrochlorides generally have been in the 10% to 15% range.

G. Crystalline L-Maleate

In another embodiment, the solid state form is a crystalline L-maleateof Compound 1. In one aspect, the crystalline L-maleate corresponds tocrystalline L-Maleate Form AAA. In another aspect, the crystallineL-maleate corresponds to crystalline L-Maleate Form BBB. L-Maleate FormAAA and L-Maleate Form BBB are further described in the Examples of theapplication.

Because L-maleic acid will react with Compound 1, the L-Maleate Form AAAand L-Maleate Form BBB generally are less chemically stable than theAmorphous Freebase, the Freebase Hydrate Form C, and the TartrateHydrate and do not exhibit pharmaceutically acceptable stability for useas an active ingredient in a pharmaceutical dosage form.

H. Crystalline Purity

In additional embodiments of the solid state forms discussed above, thesolid state form has a pharmaceutically acceptable crystalline purity(or a pharmaceutically acceptable amorphous purity in the case of theAmorphous Freebase). For example, in one aspect, Compound 1 comprises atleast about 75% by weight of the desired solid state form. In anotheraspect, at least 80% by weight is the desired solid state form. Inanother aspect, at least 85% by weight is the desired solid state form.In another aspect, at least 90% by weight is the desired solid stateform. In another aspect, at least 95% by weight is the desired solidstate form. In another aspect, at least 96% by weight is the desiredsolid state form. In another aspect, at least 97% by weight is thedesired solid state form. In another aspect, at least 98% by weight isthe desired solid state form. In another aspect, at least 99% by weightis the desired solid state form. In another aspect, Compound 1 ispresent as the substantially crystalline pure (or amorphous pure in thecase of the Amorphous Freebase) solid state form. In a preferred aspect,the solid state form is the Amorphous Freebase. In another aspect, thesolid state form is Freebase Anhydrate Form D. In a more preferredaspect, the solid state form is the Freebase Hydrate Form B. In aparticularly preferred aspect, the solid state form is the FreebaseHydrate Form C. In a preferred aspect, the solid state form is theTartrate Hydrate.

IV. METHODS OF TREATMENT

The present disclosure also relates to methods of treating aJAK-associated condition in a subject, particularly a human subjectsuffering from or susceptible to the condition, comprising administeringto the subject a therapeutically effective amount of Compound 1 freebaseor a pharmaceutically acceptable salt thereof or one or more solid stateforms of Compound 1 as described in the present disclosure. Anotheraspect of the disclosure relates to Compound 1 freebase or apharmaceutically acceptable salt thereof or one or more solid stateforms of Compound 1 as described in the present disclosure for use intreatment of a JAK-associated condition in a subject, particularly in ahuman subject suffering from or susceptible to the condition, the usecomprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or one or more solid state forms of Compound 1. In one aspect,the condition is a JAK-1-associated condition. In another aspect, thesolid state form is the Amorphous Freebase. In another aspect, the solidstate form is the Freebase Hydrate Form B. In another aspect, the solidstate form is the Freebase Hydrate Form C. In another aspect, the solidstate form is the Tartrate Hydrate. In another aspect, the solid stateform is the Freebase Anhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of immunomodulation,inflammation, and proliferative disorders (such as cancer) in a subject,wherein the method comprises administering to the subject, particularlya human subject suffering from or susceptible to the condition, atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of a conditionselected from the group consisting of immunomodulation, inflammation,and proliferative disorders (such as cancer) in a subject, particularlyin a human subject suffering from or susceptible to the condition, theuse comprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In one aspect, the solidstate form is the Amorphous Freebase. In another aspect, the solid stateform is the Freebase Anhydrate Form D. In another aspect, the solidstate form is the Freebase Hydrate Form B. In another aspect, the solidstate form is the Freebase Hydrate Form C. In another aspect, the solidstate form is the Tartrate Hydrate.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of rheumatoid arthritis,multiple sclerosis, experimental allergic encephalomyelitis, systemiclupus erythematosus, Crohn's disease, atopic dermatitis, vasculitis,cardiomyopathy, psoriasis, Reiter's syndrome, glomerulonephritis,ulcerative colitis, allergic asthma, insulin-dependent diabetes,peripheral neuropathy, uveitis, fibrosing alveolitis, type I diabetes,juvenile diabetes, juvenile arthritis, Castleman disease, neutropenia,endometriosis, autoimmune thyroid disease, sperm and testicularautoimmunity, scleroderma, axonal and neuronal neuropathies, allergicrhinitis, Sjogren's syndrome, hemolytic anemia, Graves' disease,Hashimoto's thyroiditis, IgA nephropathy, amyloidosis, ankylosingspondylitis, Behcet's disease, sarcoidosis, vesiculobullous dermatosis,myositis, primary biliary cirrhosis, polymyalgia rheumatica, autoimmuneimmunodeficiency, Chagas disease, Kawasaki syndrome, psoriaticarthritis, celiac sprue, myasthenia gravis, autoimmune myocarditis,POEMS syndrome, and chronic fatigue syndrome in a subject, wherein themethod comprises administering to the subject, particularly a humansubject suffering from or susceptible to the condition, atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of a conditionselected from the group consisting of rheumatoid arthritis, multiplesclerosis, experimental allergic encephalomyelitis, systemic lupuserythematosus, Crohn's disease, atopic dermatitis, vasculitis,cardiomyopathy, psoriasis, Reiter's syndrome, glomerulonephritis,ulcerative colitis, allergic asthma, insulin-dependent diabetes,peripheral neuropathy, uveitis, fibrosing alveolitis, type I diabetes,juvenile diabetes, juvenile arthritis, Castleman disease, neutropenia,endometriosis, autoimmune thyroid disease, sperm and testicularautoimmunity, scleroderma, axonal and neuronal neuropathies, allergicrhinitis, Sjogren's syndrome, hemolytic anemia, Graves' disease,Hashimoto's thyroiditis, IgA nephropathy, amyloidosis, ankylosingspondylitis, Behcet's disease, sarcoidosis, vesiculobullous dermatosis,myositis, primary biliary cirrhosis, polymyalgia rheumatica, autoimmuneimmunodeficiency, Chagas disease, Kawasaki syndrome, psoriaticarthritis, celiac sprue, myasthenia gravis, autoimmune myocarditis,POEMS syndrome, and chronic fatigue syndrome in a subject, particularlyin a human subject suffering from or susceptible to the condition, theuse comprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In one aspect, the solidstate form is the Amorphous Freebase. In another aspect, the solid stateform is the Freebase Hydrate Form B. In another aspect, the solid stateform is the Freebase Hydrate Form C. In another aspect, the solid stateform is the Tartrate Hydrate. In another aspect, the solid state form isthe Freebase Anhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of rheumatoid arthritis(including moderate to severe rheumatoid arthritis), systemic lupuserythematosus, multiple sclerosis, Crohn's disease (including moderateto severe Crohn's disease), psoriasis (including moderate to severechronic plaque psoriasis), ulcerative colitis (including moderate tosevere ulcerative colitis), ankylosing spondylitis, psoriatic arthritis,juvenile idiopathic arthritis (including moderate to severepolyarticular juvenile idiopathic arthritis), diabetic nephropathy, dryeye syndrome, Sjogren's syndrome, alopecia areata, vitiligo, and atopicdermatitis in a subject, wherein the method comprises administering tothe subject, particularly a human subject suffering from or susceptibleto the condition, a therapeutically effective amount of Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of a conditionselected from the group consisting of rheumatoid arthritis (includingmoderate to severe rheumatoid arthritis), systemic lupus erythematosus,multiple sclerosis, Crohn's disease (including moderate to severeCrohn's disease), psoriasis (including moderate to severe chronic plaquepsoriasis), ulcerative colitis (including moderate to severe ulcerativecolitis), ankylosing spondylitis, psoriatic arthritis, juvenileidiopathic arthritis (including moderate to severe polyarticularjuvenile idiopathic arthritis), diabetic nephropathy, dry eye syndrome,Sjogren's syndrome, alopecia areata, vitiligo, and atopic dermatitis ina subject, particularly in a human subject suffering from or susceptibleto the condition, the use comprising administering to the subject atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one aspect, the solid state form is the AmorphousFreebase. In another aspect, the solid state form is the FreebaseHydrate Form B. In another aspect, the solid state form is the FreebaseHydrate Form C. In another aspect, the solid state form is the TartrateHydrate. In another aspect, the solid state form is the FreebaseAnhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of an ocular condition,systemic inflammatory response syndrome, juvenile rheumatoid arthritis,systemic onset juvenile rheumatoid arthritis, type III hypersensitivityreactions, type IV hypersensitivity, inflammation of the aorta,iridocyclitis/uveitis/optic neuritis, juvenile spinal muscular atrophy,diabetic retinopathy or microangiopathy, chronic inflammation,ulcerative colitis, inflammatory bowel disease, allergic diseases,dermatitis scleroderma, acute or chronic immune disease associated withorgan transplantation, psoriatic arthropathy, ulcerative coliticarthropathy, autoimmune bullous disease, autoimmune haemolytic anaemia,rheumatoid arthritis associated interstitial lung disease, systemiclupus erythematosus associated lung disease,dermatomyositis/polymyositis associated lung disease, Sjogren'ssyndrome/disease associated lung disease, ankylosing spondylitis andankylosing spondylitis-associated lung disease, autoimmune hepatitis,type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis),type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmunemediated hypoglycemia, psoriasis type 1, psoriasis type 2, plaquepsoriasis, moderate to severe chronic plaque psoriasis, autoimmuneneutropenia, sperm autoimmunity, multiple sclerosis (all subtypes),acute rheumatic fever, rheumatoid spondylitis, Sjogren's syndrome, andautoimmune thrombocytopaenia in a subject, wherein the method comprisesadministering to the subject, particularly a human subject sufferingfrom or susceptible to the condition, a therapeutically effective amountof Compound 1 freebase or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1. In another aspect, the presentdisclosure relates to Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 for use intreatment of a condition selected from the group consisting of an ocularcondition, systemic inflammatory response syndrome, juvenile rheumatoidarthritis, systemic onset juvenile rheumatoid arthritis, type IIIhypersensitivity reactions, type IV hypersensitivity, inflammation ofthe aorta, iridocyclitis/uveitis/optic neuritis, juvenile spinalmuscular atrophy, diabetic retinopathy or microangiopathy, chronicinflammation, ulcerative colitis, inflammatory bowel disease, allergicdiseases, dermatitis scleroderma, acute or chronic immune diseaseassociated with organ transplantation, psoriatic arthropathy, ulcerativecolitic arthropathy, autoimmune bullous disease, autoimmune haemolyticanaemia, rheumatoid arthritis associated interstitial lung disease,systemic lupus erythematosus associated lung disease,dermatomyositis/polymyositis associated lung disease, Sjogren'ssyndrome/disease associated lung disease, ankylosing spondylitis andankylosing spondylitis-associated lung disease, autoimmune hepatitis,type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis),type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmunemediated hypoglycaemia, psoriasis type 1, psoriasis type 2, plaquepsoriasis, moderate to severe chronic plaque psoriasis, autoimmuneneutropenia, sperm autoimmunity, multiple sclerosis (all subtypes),acute rheumatic fever, rheumatoid spondylitis, Sjogren's syndrome, andautoimmune thrombocytopaenia in a subject, particularly in a humansubject suffering from or susceptible to the condition, the usecomprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In one aspect, the solidstate form is the Amorphous Freebase. In another aspect, the solid stateform is the Freebase Hydrate Form B. In another aspect, the solid stateform is the Freebase Hydrate Form C. In another aspect, the solid stateform is the Tartrate Hydrate. In another aspect, the solid state form isthe Freebase Anhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of rheumatoid arthritis,juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis,psoriasis, plaque psoriasis, nail psoriasis, psoriatic arthritis,ankylosing spondylitis, alopecia areata, hidradenitis suppurativa,atopic dermatitis, and systemic lupus erythematosus in a subject,wherein the method comprises administering to the subject atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of a conditionselected from the group consisting of rheumatoid arthritis, juvenileidiopathic arthritis, Crohn's disease, ulcerative colitis, psoriasis,plaque psoriasis, nail psoriasis, psoriatic arthritis, ankylosingspondylitis, alopecia areata, hidradenitis suppurativa, atopicdermatitis, and systemic lupus erythematosus in a subject, particularlyin a human subject suffering from or susceptible to the condition, theuse comprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a solid state form of Compound 1. Inone aspect, the solid state form is the Amorphous Freebase. In anotheraspect, the solid state form is the Freebase Hydrate Form B. In anotheraspect, the solid state form is the Freebase Hydrate Form C. In anotheraspect, the solid state form is the Tartrate Hydrate. In another aspect,the solid state form is the Freebase Anhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of rheumatoid arthritis,Crohn's disease, ankylosing spondylitis, psoriatic arthritis, psoriasis,ulcerative colitis, systemic lupus erythematosus, lupus nephritis,diabetic nephropathy, dry eye syndrome, Sjogren's syndrome, alopeciaareata, vitiligo, and atopic dermatitis in a subject, wherein the methodcomprises administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In another aspect, thepresent disclosure relates to Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 for use intreatment of a condition selected from the group consisting ofrheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriaticarthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus,lupus nephritis, diabetic nephropathy, dry eye syndrome, Sjogren'ssyndrome, alopecia areata, vitiligo, and atopic dermatitis in a subject,particularly in a human subject suffering from or susceptible to thecondition, the use comprising administering to the subject atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one aspect, the solid state form is the AmorphousFreebase. In another aspect, the solid state form is the FreebaseHydrate Form B. In another aspect, the solid state form is the FreebaseHydrate Form C. In another aspect, the solid state form is the TartrateHydrate. In another aspect, the solid state form is the FreebaseAnhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatingarthritis in a subject, wherein the method comprises administering tothe subject a therapeutically effective amount of Compound 1 freebase ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of arthritis in asubject, particularly in a human subject suffering from or susceptibleto arthritis, the use comprising administering to the subject atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one aspect, the arthritis is selected from the groupconsisting of rheumatoid arthritis, juvenile idiopathic arthritis, andpsoriatic arthritis. In another aspect, the arthritis is rheumatoidarthritis. In another aspect, the arthritis is juvenile idiopathicarthritis. In another aspect, the arthritis is psoriatic arthritis. Inanother aspect, the solid state form is the Amorphous Freebase. Inanother aspect, the solid state form is the Freebase Hydrate Form B. Inanother aspect, the solid state form is the Freebase Hydrate Form C. Inanother aspect, the solid state form is the Tartrate Hydrate. In anotheraspect, the solid state form is the Freebase Anhydrate Form D. Inanother aspect, the solid state form is the Freebase Solvate Form A. Inanother aspect, the solid state form is the Hydrochloride Solvate formAA. In another aspect, the solid state form is the Hydrochloride SolvateForm BB. In another aspect, the solid state form is the HydrochlorideSolvate Form CC. In another aspect, the solid state form is theL-Maleate Form AAA. In another aspect, the solid state form is theL-Maleate Form BBB.

In one embodiment, the present disclosure relates to methods of treatinga spondyloarthropathy in a subject, wherein the method comprisesadministering to the subject a therapeutically effective amount ofCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1. In another aspect, the presentdisclosure relates to Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 for use intreatment of spondyloarthropathy, particularly in a human subjectsuffering from or susceptible to spondyloarthropathy, the use comprisingadministering to the subject a therapeutically effective amount ofCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1. In one aspect, the spondyloarthropathyis ankylosing spondylitis. In another aspect, the solid state form isthe Amorphous Freebase. In another aspect, the solid state form is theFreebase Hydrate Form B. In another aspect, the solid state form is theFreebase Hydrate Form C. In another aspect, the solid state form is theTartrate Hydrate. In another aspect, the solid state form is theFreebase Anhydrate Form D. In another aspect, the solid state form isthe Freebase Solvate Form A. In another aspect, the solid state form isthe Hydrochloride Solvate form AA. In another aspect, the solid stateform is the Hydrochloride Solvate Form BB. In another aspect, the solidstate form is the Hydrochloride Solvate Form CC. In another aspect, thesolid state form is the L-Maleate Form AAA. In another aspect, the solidstate form is the L-Maleate Form BBB.

In one embodiment, the present disclosure relates to methods of treatinga gastrointestinal condition in a subject, wherein the method comprisesadministering to the subject a therapeutically effective amount ofCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1. In another aspect, the presentdisclosure relates to Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 for use intreatment of a gastrointestinal condition, particularly in a humansubject suffering from or susceptible to a gastrointestinal condition,the use comprising administering to the subject a therapeuticallyeffective amount of Compound 1 freebase or a pharmaceutically acceptablesalt thereof or a solid state form of Compound 1. In one aspect, thegastrointestinal condition is selected from the group consisting ofCrohn's disease and ulcerative colitis. In another aspect, thegastrointestinal condition is Crohn's disease. In another aspect, thegastrointestinal condition is ulcerative colitis. In another aspect, thesolid state form is the Amorphous Freebase. In another aspect, the solidstate form is the Freebase Hydrate Form B. In another aspect, the solidstate form is the Freebase Hydrate Form C. In another aspect, the solidstate form is the Tartrate Hydrate. In another aspect, the solid stateform is the Freebase Anhydrate Form D. In another aspect, the solidstate form is the Freebase Solvate Form A. In another aspect, the solidstate form is the Hydrochloride Solvate form AA. In another aspect, thesolid state form is the Hydrochloride Solvate Form BB. In anotheraspect, the solid state form is the Hydrochloride Solvate Form CC. Inanother aspect, the solid state form is the L-Maleate Form AAA. Inanother aspect, the solid state form is the L-Maleate Form BBB.

In one embodiment, the present disclosure relates to methods of treatinga skin condition, wherein the method comprises administering to thesubject a therapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of a skin condition,particularly in a human subject suffering from or susceptible to a skincondition, the use comprising administering to the subject atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one aspect, the skin condition is selected from the groupconsisting of psoriasis, plaque psoriasis, nail psoriasis, andhidradenitis suppurativa. In another aspect, the skin condition ispsoriasis. In another aspect, the skin condition is plaque psoriasis. Inanother aspect, the skin condition is nail psoriasis. In another aspect,the skin condition is hidradenitis suppurativa. In another aspect, theskin condition is atopic dermatitis. In another aspect, the solid stateform is the Amorphous Freebase. In another aspect, the solid state formis the Freebase Hydrate Form B. In another aspect, the solid state formis the Freebase Hydrate Form C. In another aspect, the solid state formis the Tartrate Hydrate. In another aspect, the solid state form is theFreebase Anhydrate Form D. In another aspect, the solid state form isthe Freebase Solvate Form A. In another aspect, the solid state form isthe Hydrochloride Solvate form AA. In another aspect, the solid stateform is the Hydrochloride Solvate Form BB. In another aspect, the solidstate form is the Hydrochloride Solvate Form CC. In another aspect, thesolid state form is the L-Maleate Form AAA. In another aspect, the solidstate form is the L-Maleate Form BBB.

The therapeutically effective dose level for any particular subject willdepend upon the specific situation and can depend upon a variety offactors including the type, age, weight, sex, diet, and condition of thesubject being treated; the severity of the pathological condition;activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thesubject; the route of administration; the duration of the treatment;pharmacological considerations, such as the activity, efficacy,pharmacokinetic, and toxicology profiles of the particular compound orsalt used; whether a drug delivery system is utilized; drugs used incombination or coincidental with the specific compound employed; andlike factors well-known in the medical arts. An ordinarily skilledphysician provided with the disclosure of the present application willbe able to determine appropriate dosages and regimens for administrationof the therapeutic agent to the subject, and to adjust such dosages andregimens as necessary during the course of treatment, in accordance withmethods well-known in the therapeutic arts. It is well within the skillof the art to start doses of the compound at levels lower than requiredto achieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved. Thus, the dosage regimenactually employed can vary widely, and therefore, can derive from thepreferred dosage regimen set forth below.

The total daily dose of the solid state form (administered in single ordivided doses) typically is from about 0.001 to about 100 mg/kg, or fromabout 0.001 to about 30 mg/kg, or from about 0.001 to about 15 mg/kg. Inanother embodiment, the total daily dose is from about 0.01 to about 10mg/kg (i.e., mg of the compound or salt per kg body weight). Dosage unitcompositions can contain such amounts or submultiples thereof to make upthe daily dose. In many instances, the administration of the compound orsalt will be repeated a plurality of times. Multiple doses per daytypically may be used to increase the total daily dose, if desired.

In one embodiment, the daily dose of the solid state form administeredto the subject is from about 0.01 mg to about 3000 mg. In one aspect,the daily dose is from about 0.1 mg to about 1000 mg. In another aspect,the daily dose is from is from about 1 mg to about 500 mg. In anotheraspect, the daily dose is from about 1 mg to about 250 mg. In anotheraspect, the daily dose is from about 1 mg to about 100 mg. In anotheraspect, the daily dose is from about 1 mg to about 50 mg. In anotheraspect, the daily dose is from about 1 mg to about 45 mg. In anotheraspect, the daily dose is from about 1 mg to about 30 mg. In anotheraspect, the daily dose is from about 1 mg to about 25 mg. In anotheraspect, the daily dose is from about 1 mg to about 24 mg. In anotheraspect, the daily dose is from about 1 mg to about 15 mg. In anotheraspect, the daily dose is from about 1 mg to about 7.5 mg. In anotheraspect, the daily dose is from about 25 mg to about 50 mg. In anotheraspect, the daily dose is from about 1 mg to about 10 mg. In anotheraspect, the daily dose is from about 10 mg to about 20 mg. In anotheraspect, the daily dose is from about 20 mg to about 30 mg. In anotheraspect, the daily dose is from about 30 mg to about 40 mg. In anotheraspect, the daily dose is from about 7.5 mg to about 45 mg. In anotheraspect, the daily dose is from about 15 mg to about 30 mg. In anotheraspect, the daily dose is about 3 mg. In another aspect, the daily doseis about 6 mg. In another aspect, the daily dose is about 7.5 mg. Inanother aspect, the daily dose is about 12 mg. In another aspect, thedaily dose is about 15 mg. In another aspect, the daily dose is about 18mg. In another aspect, the daily dose is about 24 mg. In another aspect,the daily dose is about 30 mg. In another aspect, the daily dose isabout 36 mg. In another aspect, the daily dose is about 45 mg.

In one embodiment, a dose of about 3 mg, about 6 mg, about 12 mg, orabout 24 mg per unit dosage form (e.g., per tablet or capsule) of asolid state form of Compound 1 is administered orally BID (twice daily)in equal amounts (e.g., twice a day, about 3 mg each time) to a humansubject.

In one embodiment, the disclosure relates to a method of treating asubject having rheumatoid arthritis, the method comprising administeringto the subject about 3 mg, per unit dosage form (e.g., per tablet orcapsule) of a solid state form of Compound 1 orally BID (twice daily) inequal amounts (e.g., twice a day, about 3 mg each time). In anotheraspect, the present disclosure relates a solid state form of Compound 1for use in treating rheumatoid arthritis in a subject, particularly in ahuman subject suffering from or susceptible to rheumatoid arthritis, theuse comprising administering to the subject about 3 mg, per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1orally BID (twice daily) in equal amounts (e.g., twice a day, about 3 mgeach time).

In one embodiment, the disclosure relates to a method of treating asubject having rheumatoid arthritis, the method comprising administeringto the subject about 6 mg, per unit dosage form (e.g., per tablet orcapsule) of a solid state form of Compound 1 orally BID (twice daily) inequal amounts (e.g., twice a day, about 6 mg each time). In anotheraspect, the present disclosure relates a solid state form of Compound 1for use in treating rheumatoid arthritis in a subject, particularly in ahuman subject suffering from or susceptible to rheumatoid arthritis, theuse comprising administering to the subject about 6 mg, per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1orally BID (twice daily) in equal amounts (e.g., twice a day, about 6 mgeach time).

In one embodiment, the disclosure relates to a method of treating asubject having rheumatoid arthritis, the method comprising administeringto the subject about 12 mg, per unit dosage form (e.g., per tablet orcapsule) of a solid state form of Compound 1 orally BID (twice daily) inequal amounts (e.g., twice a day, about 12 mg each time). In anotheraspect, the present disclosure relates a solid state form of Compound 1for use in treating rheumatoid arthritis in a subject, particularly in ahuman subject suffering from or susceptible to rheumatoid arthritis, theuse comprising administering to the subject about 12 mg, per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1orally BID (twice daily) in equal amounts (e.g., twice a day, about 12mg each time).

In one embodiment, the disclosure relates to a method of treating asubject having rheumatoid arthritis, the method comprising administeringto the subject about 24 mg, per unit dosage form (e.g., per tablet orcapsule) of a solid state form of Compound 1 orally BID (twice daily) inequal amounts (e.g., twice a day, about 24 mg each time). In anotheraspect, the present disclosure relates a solid state form of Compound 1for use in treating rheumatoid arthritis in a subject, particularly in ahuman subject suffering from or susceptible to rheumatoid arthritis, theuse comprising administering to the subject about 24 mg, per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1orally BID (twice daily) in equal amounts (e.g., twice a day, about 24mg each time).

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 7.5 mg per unitdosage form (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 7.5 mg per unitdosage form (e.g., per tablet or capsule) of a solid state form ofCompound 1. In one embodiment, the methods or uses compriseadministering orally QD (once daily) to a human subject a solid stateform of Compound 1 in an amount sufficient to deliver 7.5 mg per unitdosage form (e.g., per tablet or capsule) of Compound 1 freebaseequivalent to the subject. In one embodiment, the solid state form isthe Amorphous Freebase. In one embodiment, the solid state form is theFreebase Hydrate Form B. In one embodiment, the solid state form is theFreebase Hydrate Form C. In one embodiment, the solid state form is theTartrate Hydrate. In another aspect, the solid state form is theFreebase Anhydrate Form D.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 15 mg per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 15 mg per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1.In one embodiment, the methods or uses comprise administering orally QD(once daily) to a human subject a solid state form of Compound 1 in anamount sufficient to deliver 15 mg per unit dosage form (e.g., pertablet or capsule) of Compound 1 freebase equivalent to the subject. Inone embodiment, the solid state form is the Amorphous Freebase. In oneembodiment, the solid state form is the Freebase Hydrate Form B. In oneembodiment, the solid state form is the Freebase Hydrate Form C. In oneembodiment, the solid state form is the Tartrate Hydrate. In anotheraspect, the solid state form is the Freebase Anhydrate Form D.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 24 mg of Compound 1freebase or a pharmaceutically acceptable salt thereof. The 24 mg QDdose of Compound 1 freebase or a pharmaceutically acceptable saltthereof may be administered as either a single dosage form comprisingabout 24 mg per unit dosage form (e.g., per tablet or capsule) ofCompound 1 freebase or a pharmaceutically acceptable salt thereof, ortwo dosage forms comprising about 12 mg per unit dosage form (e.g., pertablet or capsule) of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof administered simultaneously.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 24 mg of a solidstate form of Compound 1. In one embodiment, the methods or usescomprise administering orally QD (once daily) to a human subject a solidstate form of Compound 1 in an amount sufficient to deliver 24 mg ofCompound 1 freebase equivalent to the subject. The 24 mg QD dose of thesolid state form of Compound 1 may be administered as either a singledosage form comprising about 24 mg per unit dosage form (e.g., pertablet or capsule) of the solid state form of Compound 1, or two dosageforms comprising about 12 mg per unit dosage form (e.g., per tablet orcapsule) of the solid state form of Compound 1 administeredsimultaneously. In one embodiment, the solid state form is the AmorphousFreebase. In one embodiment, the solid state form is the FreebaseHydrate Form B. In one embodiment, the solid state form is the FreebaseHydrate Form C. In one embodiment, the solid state form is the TartrateHydrate. In another aspect, the solid state form is the FreebaseAnhydrate Form D.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 30 mg per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 30 mg per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1.In one embodiment, the methods or uses comprise administering orally QD(once daily) to a human subject a solid state form of Compound 1 in anamount sufficient to deliver 30 mg per unit dosage form (e.g., pertablet or capsule) of Compound 1 freebase equivalent to the subject. Inone embodiment, the solid state form is the Amorphous Freebase. In oneembodiment, the solid state form is the Freebase Hydrate Form B. In oneembodiment, the solid state form is the Freebase Hydrate Form C. In oneembodiment, the solid state form is the Tartrate Hydrate. In anotheraspect, the solid state form is the Freebase Anhydrate Form D.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 36 mg per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 36 mg per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1.In one embodiment, the methods or uses comprise administering orally QD(once daily) to a human subject a solid state form of Compound 1 in anamount sufficient to deliver 36 mg per unit dosage form (e.g., pertablet or capsule) of Compound 1 freebase equivalent to the subject. Inone embodiment, the solid state form is the Amorphous Freebase. In oneembodiment, the solid state form is the Freebase Hydrate Form B. In oneembodiment, the solid state form is the Freebase Hydrate Form C. In oneembodiment, the solid state form is the Tartrate Hydrate. In anotheraspect, the solid state form is the Freebase Anhydrate Form D.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 45 mg per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 45 mg per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1.In one embodiment, the methods or uses comprise administering orally QD(once daily) to a human subject a solid state form of Compound 1 in anamount sufficient to deliver 45 mg per unit dosage form (e.g., pertablet or capsule) of Compound 1 freebase equivalent to the subject. Inone embodiment, the solid state form is the Amorphous Freebase. In oneembodiment, the solid state form is the Freebase Hydrate Form B. In oneembodiment, the solid state form is the Freebase Hydrate Form C. In oneembodiment, the solid state form is the Tartrate Hydrate. In anotheraspect, the solid state form is the Freebase Anhydrate Form D.

In certain embodiments, Compound 1 freebase or a pharmaceuticallyacceptable salt thereof and/or solid state forms thereof can be used totreat rheumatoid arthritis (RA), including reducing signs and symptomsof RA, inducing a major clinical response, inhibiting the progression ofor treating structural damage associated with RA, and improving physicalfunction in adult subjects, such as adult subjects with moderately toseverely active RA. In one embodiment, Compound 1 freebase or apharmaceutically acceptable salt thereof and/or solid state formsthereof are used to treat RA in adult subjects. In one embodiment,Compound 1 freebase or a pharmaceutically acceptable salt thereof and/orsolid state forms thereof are used to reduce signs and symptoms of RA inadult subjects. In one embodiment, Compound 1 freebase or apharmaceutically acceptable salt thereof and/or solid state formsthereof induce a major clinical response in adult subjects with RA. Inone embodiment, Compound 1 freebase or a pharmaceutically acceptablesalt thereof and/or solid state forms thereof are used to inhibit theprogression of structural damage associated with RA in adult subjects.In one embodiment, Compound 1 freebase and/or solid state forms thereofare used to treat structural damage associated with RA in adultsubjects. In one embodiment, Compound 1 freebase or a pharmaceuticallyacceptable salt thereof and/or solid state forms thereof are used toimprove physical function in adult subjects. In one embodiment, theadult subjects have RA. In another embodiment, the adult subjects havemoderately to severely active RA.

Compound 1 freebase or a pharmaceutically acceptable salt thereof orsolid state forms thereof may be used alone, or in combination withmethotrexate or other non-biologic disease-modifying anti-rheumaticdrugs (DMARDs), and/or in combination with anti-TNFα biological agents,such as TNF antagonists like chimeric, humanized or human TNFantibodies, adalimumab (such as HUMIRA™ brand adalimumab), infliximabsuch as CA2 (REMICADE™ brand infliximab), golimumab such as SIMPONI™(golimumab), certolizumab pegol such as CIMZIA™, tocilizumab such asACTEMRA™, CDP 571, and soluble p55 or p75 TNF receptors, derivatives,thereof, etanercept such as p75TNFR1gG (ENBREL™ brand etanercept) orp55TNFR1gG (lenercept).

Patients having active rheumatoid arthritis (RA) may be diagnosedaccording to 1987-revised American College of Rheumatology (ACR)classification criteria or the 2010 ACR/EULAR criteria. In certainembodiments, RA may be diagnosed based on patients having at least 6swollen and 6 tender joints. In certain embodiments, patients treatablewith Compound 1 or solid state forms thereof may include those who havefailed therapy with at least one (e.g., at least one but no more thanfour) DMARDs and/or have inadequate response to methotrexate,adalimumab, infliximab, etanercept, or other anti-TNFα biologicalagents, or non-anti-TNF biologics.

In certain embodiments, Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or solid state forms thereof halt diseaseprogression, and/or relieves at least a symptom of the disease, whichmay be detected or monitored by X-ray results, including radiographicprogression of joint damage.

In certain embodiments, therapeutic efficacy can be measured byimprovements in ACR20, ACR50, and/or ACR70, either in individualpatients or a population of patients in need of treatment. In certainembodiments, statistically significant improvement (as compared placeboor untreated control) over a treatment period (e.g., 1 week, 2 weeks, 4weeks, 6 weeks, 8 weeks, 12 weeks, 2 months, 3 months, 6 months, 1 year,2 years, 5 years, 10 years or more) in one or more of the ACR criteriais achieved. Statistical significance is manifested by a p value of lessthan 0.05, or less than 0.01.

Components of the ACR responses are well known in the art, and mayinclude the median number of tender joints, the median number of swollenjoints, physician global assessment such as one measured by visualanalog scale (VAS), patient global assessment such as one measured byvisual analog scale, pain such as one measured by visual analog scale,disability index of the Health Assessment Questionnaire (HAQ-DI score),and C-reactive protein (CRP) (mg/dL).

In certain embodiments, an ACR20 response is determined based on a 20%or greater improvement in tender joint count (TJC) and swollen jointcount (SJC) and greater than or equal to 3 of the 5 measures ofPatient's Assessment of Pain (VAS), Patient's Global Assessment ofDisease Activity (VAS), Physician's Global Assessment of DiseaseActivity (VAS), HAQ-DI, or high sensitivity C-reactive protein (hsCRP).In some embodiments, an ACR50 response is determined based on a 50% orgreater improvement in TJC and SJC and greater than or equal to 3 of the5 measures of Patient's Assessment of Pain (VAS), Patient's GlobalAssessment of Disease Activity (VAS), Physician's Global Assessment ofDisease Activity (VAS), HAQ-DI, or hsCRP. An ACR70 response isdetermined based on a 70% or greater improvement in TJC and SJC andgreater than or equal to 3 of the 5 measures of Patient's Assessment ofPain (VAS), Patient's Global Assessment of Disease Activity (VAS),Physician's Global Assessment of Disease Activity (VAS), HAQ-DI, orhsCRP. In certain embodiments, the ACR20, ACR50, or ACR70 responseoccurs by week 12 of treatment.

In certain embodiments, a DAS28 (disease activity score based on the 28joints examined) score is determined as a composite score derived fromfour of the following measures: examination of joints for swelling andtenderness, global scores of pain and overall status, blood markers ofinflammation (e.g. ESR (erythrocyte sedimentation rate) and CRP (Creactive protein), referred to herein as DAS28(CRP)), questionnaires(e.g. the HAQ (health assessment questionnaire) which assess function)and X-rays and other imaging techniques such as ultrasound and MRI.

In certain embodiments, structural joint damage can be assessedradiographically and expressed as change in Total Sharp Score (TSS) andits components, the erosion score and Joint Space Narrowing (JSN) score,for example, at week 12 compared to baseline, or at week 24 as comparedto baseline.

In certain embodiments, improvement in signs and symptoms of the diseasecan be measured by patient physical function response, such asdisability index of Health Assessment Questionnaire (HAQ-DI), and/or thehealth-outcomes as assessed by The Short Form Health Survey (SF 36). Inone embodiment, improvement in signs and symptoms of the disease ismeasured by HAQ-DI, including the minimal clinically importantdifference (MCID) of −0.22. Improvement can also be measured by one orboth of Physical Component Summary (PCS) and the Mental ComponentSummary (MCS). Improvements can further be measured by Work InstabilityScale for RA (RA-WIS) (see Gilworth et al., Arthritis & Rheumatism(Arthritis Care & Research) 49(3): 349-354, 2003, incorporated byreference).

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 7.5 mg, per unit dosage form(e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). Inanother aspect, the present disclosure relates to Compound 1 freebase ora pharmaceutically acceptable salt thereof for use in treatment ofrheumatoid arthritis in a subject, particularly in a human subjectsuffering from or susceptible to rheumatoid arthritis, the usecomprising administering to the subject about 7.5 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). In oneembodiment, the subject has moderately to severely active rheumatoidarthritis. In one embodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 7.5 mg, per unit dosage form(e.g., per tablet or capsule) of a solid state form of Compound 1 orallyQD (once daily). In one embodiment, the method comprising administeringto the subject a solid state form of Compound 1 orally QD (once daily)in an amount sufficient to deliver 7.5 mg, per unit dosage form (e.g.,per tablet or capsule) of Compound 1 freebase equivalent to the subject.In another aspect, the present disclosure relates to a solid state formof Compound 1 for use in treatment of rheumatoid arthritis in a subject,particularly in a human subject suffering from or susceptible torheumatoid arthritis, the use comprising administering to the subjectabout 7.5 mg, per unit dosage form (e.g., per tablet or capsule) of asolid state form of Compound 1 orally QD (once daily). In oneembodiment, the solid state form delivers about 7.5 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase equivalent tothe subject. In one embodiment, the solid state form is the FreebaseHydrate Form B. In one embodiment, the solid state form is the FreebaseHydrate Form C. In one embodiment, the solid state form is the TartrateHydrate. In one embodiment, the solid state form is Freebase AnhydrateForm D. In one embodiment, the subject has moderately to severely activerheumatoid arthritis. In another aspect, the solid state form is theFreebase Solvate Form A. In another aspect, the solid state form is theHydrochloride Solvate form AA. In another aspect, the solid state formis the Hydrochloride Solvate Form BB. In another aspect, the solid stateform is the Hydrochloride Solvate Form CC. In another aspect, the solidstate form is the L-Maleate Form AAA. In another aspect, the solid stateform is the L-Maleate Form BBB. In one embodiment, the subject is anadult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 15 mg, per unit dosage form(e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). Inanother aspect, the present disclosure relates to Compound 1 freebase ora pharmaceutically acceptable salt thereof for use in treatment ofrheumatoid arthritis in a subject, particularly in a human subjectsuffering from or susceptible to rheumatoid arthritis, the usecomprising administering to the subject about 15 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). In oneembodiment, the subject has moderately to severely active rheumatoidarthritis. In one embodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 15 mg, per unit dosage form(e.g., per tablet or capsule) of a solid state form of Compound 1 orallyQD (once daily). In one embodiment, the method comprising administeringto the subject a solid state form of Compound 1 orally QD (once daily)in an amount sufficient to deliver 15 mg, per unit dosage form (e.g.,per tablet or capsule) of Compound 1 freebase equivalent to the subject.In another aspect, the present disclosure relates to a solid state formof Compound 1 for use in treatment of rheumatoid arthritis in a subject,particularly in a human subject suffering from or susceptible torheumatoid arthritis, the use comprising administering to the subjectabout 15 mg, per unit dosage form (e.g., per tablet or capsule) of asolid state form of Compound 1 orally QD (once daily). In oneembodiment, the solid state form delivers about 15 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase equivalent tothe subject. In one embodiment, the solid state form is the FreebaseHydrate Form B. In one embodiment, the solid state form is the FreebaseHydrate Form C. In one embodiment, the solid state form is the TartrateHydrate. In one embodiment, the solid state form is Freebase AnhydrateForm D. In one embodiment, the subject has moderately to severely activerheumatoid arthritis. In another aspect, the solid state form is theFreebase Solvate Form A. In another aspect, the solid state form is theHydrochloride Solvate form AA. In another aspect, the solid state formis the Hydrochloride Solvate Form BB. In another aspect, the solid stateform is the Hydrochloride Solvate Form CC. In another aspect, the solidstate form is the L-Maleate Form AAA. In another aspect, the solid stateform is the L-Maleate Form BBB. In one embodiment, the subject is anadult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 24 mg of Compound 1 freebaseor a pharmaceutically acceptable salt thereof orally QD (once daily). Inanother aspect, the present disclosure relates to Compound 1 freebase ora pharmaceutically acceptable salt thereof for use in treatment ofrheumatoid arthritis in a subject, particularly in a human subjectsuffering from or susceptible to rheumatoid arthritis, the usecomprising administering to the subject about 24 mg of Compound 1freebase or a pharmaceutically acceptable salt thereof orally QD (oncedaily). The 24 mg dose of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof may be administered as either a single dosageform comprising about 24 mg per unit dosage form (e.g., per tablet orcapsule) of Compound 1 freebase or a pharmaceutically acceptable saltthereof, or two dosage forms comprising about 12 mg per unit dosage form(e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof administered simultaneously. Inone embodiment, the subject has moderately to severely active rheumatoidarthritis. In one embodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 24 mg of a solid state formof Compound 1 orally QD (once daily). In one embodiment, the methodcomprising administering to the subject a solid state form of Compound 1orally QD (once daily) in an amount sufficient to deliver 24 mg ofCompound 1 freebase equivalent to the subject. In another aspect, thepresent disclosure relates to a solid state form of Compound 1 for usein treatment of rheumatoid arthritis in a subject, particularly in ahuman subject suffering from or susceptible to rheumatoid arthritis, theuse comprising administering to the subject about 24 mg of a solid stateform of Compound 1 orally QD (once daily). In one embodiment, the solidstate form delivers about 24 mg of Compound 1 freebase equivalent to thesubject. The 24 mg dose of the solid state form of Compound 1 may beadministered as either a single dosage form comprising about 24 mg perunit dosage form (e.g., per tablet or capsule) of the solid state formof Compound 1, or two dosage forms comprising about 12 mg per unitdosage form (e.g., per tablet or capsule) of the solid state form ofCompound 1 administered simultaneously. In one embodiment, the solidstate form is the Freebase Hydrate Form B. In one embodiment, the solidstate form is the Freebase Hydrate Form C. In one embodiment, the solidstate form is the Tartrate Hydrate. In one embodiment, the solid stateform is the Freebase Anhydrate Form D. In another aspect, the solidstate form is the Freebase Solvate Form A. In another aspect, the solidstate form is the Hydrochloride Solvate form AA. In another aspect, thesolid state form is the Hydrochloride Solvate Form BB. In anotheraspect, the solid state form is the Hydrochloride Solvate Form CC. Inanother aspect, the solid state form is the L-Maleate Form AAA. Inanother aspect, the solid state form is the L-Maleate Form BBB. In oneembodiment, the subject has moderately to severely active rheumatoidarthritis. In one embodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 30 mg, per unit dosage form(e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). Inanother aspect, the present disclosure relates to Compound 1 freebase ora pharmaceutically acceptable salt thereof for use in treatment ofrheumatoid arthritis in a subject, particularly in a human subjectsuffering from or susceptible to rheumatoid arthritis, the usecomprising administering to the subject about 30 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). In oneembodiment, the subject has moderately to severely active rheumatoidarthritis. In one embodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 30 mg, per unit dosage form(e.g., per tablet or capsule) of a solid state form of Compound 1 orallyQD (once daily). In one embodiment, the method comprising administeringto the subject a solid state form of Compound 1 orally QD (once daily)in an amount sufficient to deliver 30 mg, per unit dosage form (e.g.,per tablet or capsule) of Compound 1 freebase equivalent to the subject.In another aspect, the present disclosure relates to a solid state formof Compound 1 for use in treatment of rheumatoid arthritis in a subject,particularly in a human subject suffering from or susceptible torheumatoid arthritis, the use comprising administering to the subjectabout 30 mg, per unit dosage form (e.g., per tablet or capsule) of asolid state form of Compound 1 orally QD (once daily). In oneembodiment, the solid state form delivers about 30 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase equivalent tothe subject. In one embodiment, the solid state form is the FreebaseHydrate Form B. In one embodiment, the solid state form is the FreebaseHydrate Form C. In one embodiment, the solid state form is the TartrateHydrate. In one embodiment, the solid state form is the FreebaseAnhydrate Form D. In one embodiment, the subject has moderately toseverely active rheumatoid arthritis. In another aspect, the solid stateform is the Freebase Solvate Form A. In another aspect, the solid stateform is the Hydrochloride Solvate form AA. In another aspect, the solidstate form is the Hydrochloride Solvate Form BB. In another aspect, thesolid state form is the Hydrochloride Solvate Form CC. In anotheraspect, the solid state form is the L-Maleate Form AAA. In anotheraspect, the solid state form is the L-Maleate Form BBB. In oneembodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 36 mg, per unit dosage form(e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). Inanother aspect, the present disclosure relates to Compound 1 freebase ora pharmaceutically acceptable salt thereof for use in treatment ofrheumatoid arthritis in a subject, particularly in a human subjectsuffering from or susceptible to rheumatoid arthritis, the usecomprising administering to the subject about 36 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). In oneembodiment, the subject has moderately to severely active rheumatoidarthritis. In one embodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 36 mg, per unit dosage form(e.g., per tablet or capsule) of a solid state form of Compound 1 orallyQD (once daily). In one embodiment, the method comprising administeringto the subject a solid state form of Compound 1 orally QD (once daily)in an amount sufficient to deliver 36 mg, per unit dosage form (e.g.,per tablet or capsule) of Compound 1 freebase equivalent to the subject.In another aspect, the present disclosure relates to a solid state formof Compound 1 for use in treatment of rheumatoid arthritis in a subject,particularly in a human subject suffering from or susceptible torheumatoid arthritis, the use comprising administering to the subjectabout 36 mg, per unit dosage form (e.g., per tablet or capsule) of asolid state form of Compound 1 orally QD (once daily). In oneembodiment, the solid state form delivers about 36 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase equivalent tothe subject. In one embodiment, the solid state form is the FreebaseHydrate Form B. In one embodiment, the solid state form is the FreebaseHydrate Form C. In one embodiment, the solid state form is the TartrateHydrate. In one embodiment, the solid state form is the FreebaseAnhydrate Form D. In one embodiment, the subject has moderately toseverely active rheumatoid arthritis. In another aspect, the solid stateform is the Freebase Solvate Form A. In another aspect, the solid stateform is the Hydrochloride Solvate form AA. In another aspect, the solidstate form is the Hydrochloride Solvate Form BB. In another aspect, thesolid state form is the Hydrochloride Solvate Form CC. In anotheraspect, the solid state form is the L-Maleate Form AAA. In anotheraspect, the solid state form is the L-Maleate Form BBB. In oneembodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 45 mg, per unit dosage form(e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). Inanother aspect, the present disclosure relates to Compound 1 freebase ora pharmaceutically acceptable salt thereof for use in treatment ofrheumatoid arthritis in a subject, particularly in a human subjectsuffering from or susceptible to rheumatoid arthritis, the usecomprising administering to the subject about 45 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). In oneembodiment, the subject has moderately to severely active rheumatoidarthritis. In one embodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 45 mg, per unit dosage form(e.g., per tablet or capsule) of a solid state form of Compound 1 orallyQD (once daily). In one embodiment, the method comprising administeringto the subject a solid state form of Compound 1 orally QD (once daily)in an amount sufficient to deliver 45 mg, per unit dosage form (e.g.,per tablet or capsule) of Compound 1 freebase equivalent to the subject.In another aspect, the present disclosure relates to a solid state formof Compound 1 for use in treatment of rheumatoid arthritis in a subject,particularly in a human subject suffering from or susceptible torheumatoid arthritis, the use comprising administering to the subjectabout 45 mg, per unit dosage form (e.g., per tablet or capsule) of asolid state form of Compound 1 orally QD (once daily). In oneembodiment, the solid state form delivers about 45 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase equivalent tothe subject. In one embodiment, the solid state form is the FreebaseHydrate Form B. In one embodiment, the solid state form is the FreebaseHydrate Form C. In one embodiment, the solid state form is the TartrateHydrate. In one embodiment, the solid state form is the FreebaseAnhydrate Form D. In one embodiment, the subject has moderately toseverely active rheumatoid arthritis. In another aspect, the solid stateform is the Freebase Solvate Form A. In another aspect, the solid stateform is the Hydrochloride Solvate form AA. In another aspect, the solidstate form is the Hydrochloride Solvate Form BB. In another aspect, thesolid state form is the Hydrochloride Solvate Form CC. In anotheraspect, the solid state form is the L-Maleate Form AAA. In anotheraspect, the solid state form is the L-Maleate Form BBB. In oneembodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingmoderate to severely active rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tomoderate to severely active rheumatoid arthritis, the method comprisingadministering to the subject a therapeutically effective amount ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1. In one embodiment, the methodcomprises administering to the subject about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule) of Compound 1 (freebase), or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1 in an amount sufficient todeliver to the subject about 7.5 mg or about 15 mg or about 30 mg orabout 45 mg, per unit dosage form (e.g., per tablet or capsule) ofCompound 1 freebase equivalent. In one embodiment, the method comprisesadministering to the subject about 7.5 mg or about 15 mg or about 30 mgor about 45 mg, per unit dosage form (e.g., per tablet or capsule) ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1. In one embodiment, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or the solidstate form of Compound 1 is administered to the subject orally QD (oncedaily). In another aspect, the disclosure relates to Compound 1 freebaseor a pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 (e.g., a crystalline hydrate or crystalline anhydrate), asdescribed in the present disclosure, for use in treatment of moderate toseverely active rheumatoid arthritis in an adult subject, particularlyin a human subject suffering from or susceptible to moderate to severelyactive rheumatoid arthritis, the use comprising administering to thesubject a therapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one embodiment, the solid state form is a crystallinehydrate. In one embodiment, the crystalline hydrate is the FreebaseHydrate Form B. In one embodiment, the crystalline hydrate is ahemihydrate. In one embodiment, the hemihydrate is Freebase Hydrate FormC. In one embodiment, the solid state form is a crystalline anhydrate.In one embodiment, the crystalline anhydrate is Freebase Anhydrate FormD. In one embodiment, the solid state form is the Freebase Solvate FormA. In another aspect, the solid state form is the Hydrochloride Solvateform AA. In one embodiment, the solid state form is the HydrochlorideSolvate Form BB. In one embodiment, the solid state form is theHydrochloride Solvate Form CC. In one embodiment, the solid state formis the L-Maleate Form AAA. In one embodiment, the solid state form isthe L-Maleate Form BBB. In one embodiment, the Compound 1 (freebase) ora pharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation. In oneembodiment, the formulation delivers about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg per unit dosage form (e.g., per tablet orcapsule) of Compound 1 (freebase equivalent) or a solid state form ofCompound 1 orally QD (once daily).

In one embodiment, the subject having moderate to severely activerheumatoid arthritis has, prior to treatment, at least one of thefollowing identifying characteristics: at least 6 swollen joints (basedon 66 joint counts), at least 6 tender joints (based on 68 jointcounts), high-sensitivity C-reactive protein (hsCRP) greater than theupper limit of normal (ULN), or positive test results for bothrheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP). Inone embodiment, the subject having moderate to severely activerheumatoid arthritis has, prior to treatment, at least 6 swollen joints(based on 66 joint counts) and at least 6 tender joints (based on 68joint counts). Methods for assessing tender and swollen joints areknown, and described in, for example, Scott, et al., Clinical andExperimental Rheumatology, 2014, Vol. 32 (Supp. 85), S7-S12.

Thus, in another embodiment, the present disclosure is directed to amethod of treating moderate to severely active rheumatoid arthritis inan adult subject, particularly in a human subject suffering from orsusceptible to moderate to severely active rheumatoid arthritis, themethod comprising administering to the subject a therapeuticallyeffective amount of Compound 1 (freebase), or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 (e.g., acrystalline hydrate or a crystalline anhydrate) as described herein,wherein the subject has symptoms selected from the group consisting ofat least 6 swollen joints, at least 6 tender joints, and combinationsthereof prior to treating. In one embodiment, the method comprisesadministering to the subject about 7.5 mg or about 15 mg or about 30 mgor about 45 mg, per unit dosage form (e.g., per tablet or capsule), perday of Compound 1 (freebase) or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1 in an amount sufficient todeliver to the subject about 7.5 or about 15 mg or about 30 mg or about45 mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent, wherein the subject has symptomsselected from the group consisting of at least 6 swollen joints, atleast 6 tender joints, and combinations thereof prior to treating. Inone embodiment, the method comprises administering to the subject about7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1.In another aspect, the disclosure relates to Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 (e.g., a crystalline hydrate or crystalline anhydrate), asdescribed in the present disclosure, for use in treatment of moderate toseverely active rheumatoid arthritis in an adult subject, particularlyin a human subject suffering from or susceptible to moderate to severelyactive rheumatoid arthritis, wherein the subject has symptoms selectedfrom the group consisting of at least 6 swollen joints, at least 6tender joints, and combinations thereof prior to treating, the usecomprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In one embodiment, thetherapeutically effective amount of the solid state form of Compound 1delivers to the subject about 7.5 mg or about 15 mg or about 30 mg orabout 45 mg per unit dosage form (e.g., per tablet or capsule) ofCompound 1 (freebase equivalent) or a solid state form of Compound 1orally QD (once daily). In one embodiment, the Compound 1 (freebase) ora pharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation. In oneembodiment, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the solid state form of Compound 1 is administered tothe subject orally QD (once daily). In one embodiment, the solid stateform is a crystalline hydrate. In one embodiment, the crystallinehydrate is the Freebase Hydrate Form B. In one embodiment, thecrystalline hydrate is the Freebase Hydrate Form C. In one embodiment,the solid state form is a crystalline anhydrate. In one embodiment, thecrystalline anhydrate is the Freebase Anhydrate Form D. In oneembodiment, the solid state form is Tartrate Hydrate. In one embodiment,the symptoms result from the progression of structural damage assessedby radiograph.

In one embodiment, the present disclosure is directed to a method oftreating moderate to severely active rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto moderate to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 7.5 mg, per unit dosageform (e.g., per tablet or capsule), per day of Compound 1 (freebase), ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 7.5mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent, wherein the subject has symptomsselected from the group consisting of at least 6 swollen joints, atleast 6 tender joints, and combinations thereof prior to treating. Inone embodiment, the method comprises administering to the subject about7.5 mg, per unit dosage form (e.g., per tablet or capsule), per day of asolid state form of Compound 1. In another aspect, the disclosurerelates to Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1 for use in treatment ofmoderate to severely active rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tomoderate to severely active rheumatoid arthritis, wherein the subjecthas symptoms selected from the group consisting of at least 6 swollenjoints, at least 6 tender joints, and combinations thereof prior totreating, the use comprising administering to the subject about 7.5 mg,per unit dosage form (e.g., per tablet or capsule) of Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1. In one embodiment, the solid state form is acrystalline hydrate. In one embodiment, the crystalline hydrate is theFreebase Hydrate Form B. In one embodiment, the crystalline hydrate isthe Freebase Hydrate Form C. In one embodiment, the solid state form isa crystalline anhydrate. In one embodiment, the crystalline anhydrate isthe Freebase Anhydrate Form D. In one embodiment, the solid state formis the Tartrate Hydrate. In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is administered orally QD (once daily). In one embodiment,the Compound 1 freebase or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the symptoms result from the progressionof structural damage assessed by radiograph.

In one embodiment, the present disclosure is directed to a method oftreating moderate to severely active rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto moderate to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 15 mg, per unit dosageform (e.g., per tablet or capsule), per day of Compound 1 (freebase), ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 15mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent, wherein the subject has symptomsselected from the group consisting of at least 6 swollen joints, atleast 6 tender joints, and combinations thereof prior to treating. Inone embodiment, the method comprises administering to the subject about15 mg, per unit dosage form (e.g., per tablet or capsule), per day of asolid state form of Compound 1. In another aspect, the disclosurerelates to Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1 for use in treatment ofmoderate to severely active rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tomoderate to severely active rheumatoid arthritis, wherein the subjecthas symptoms selected from the group consisting of at least 6 swollenjoints, at least 6 tender joints, and combinations thereof prior totreating, the use comprising administering to the subject about 15 mg,per unit dosage form (e.g., per tablet or capsule) of Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1. In one embodiment, the solid state form is acrystalline hydrate. In one embodiment, the crystalline hydrate is theFreebase Hydrate Form B. In one embodiment, the crystalline hydrate isthe Freebase Hydrate Form C. In one embodiment, the solid state form isa crystalline anhydrate. In one embodiment, the crystalline anhydrate isthe Freebase Anhydrate Form D. In one embodiment, the solid state formis the Tartrate Hydrate. In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is administered orally QD (once daily). In one embodiment,the Compound 1 freebase or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the symptoms result from the progressionof structural damage assessed by radiograph.

In one embodiment, the present disclosure is directed to a method oftreating moderate to severely active rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto moderate to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 30 mg, per unit dosageform (e.g., per tablet or capsule), per day of Compound 1 (freebase), ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 30mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent, wherein the subject has symptomsselected from the group consisting of at least 6 swollen joints, atleast 6 tender joints, and combinations thereof prior to treating. Inone embodiment, the method comprises administering to the subject about30 mg, per unit dosage form (e.g., per tablet or capsule), per day of asolid state form of Compound 1. In another aspect, the disclosurerelates to Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1 for use in treatment ofmoderate to severely active rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tomoderate to severely active rheumatoid arthritis, wherein the subjecthas symptoms selected from the group consisting of at least 6 swollenjoints, at least 6 tender joints, and combinations thereof prior totreating, the use comprising administering to the subject about 30 mg,per unit dosage form (e.g., per tablet or capsule) of Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1. In one embodiment, the solid state form is acrystalline hydrate. In one embodiment, the crystalline hydrate is theFreebase Hydrate Form B. In one embodiment, the crystalline hydrate isthe Freebase Hydrate Form C. In one embodiment, the solid state form isa crystalline anhydrate. In one embodiment, the crystalline anhydrate isthe Freebase Anhydrate Form D. In one embodiment, the solid state formis the Tartrate Hydrate. In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is administered orally QD (once daily). In one embodiment,the Compound 1 freebase or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the symptoms result from the progressionof structural damage assessed by radiograph.

In one embodiment, the present disclosure is directed to a method oftreating moderate to severely active rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto moderate to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 45 mg, per unit dosageform (e.g., per tablet or capsule), per day of Compound 1 (freebase), ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 45mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent, wherein the subject has symptomsselected from the group consisting of at least 6 swollen joints, atleast 6 tender joints, and combinations thereof prior to treating. Inone embodiment, the method comprises administering to the subject about45 mg, per unit dosage form (e.g., per tablet or capsule), per day of asolid state form of Compound 1. In another aspect, the disclosurerelates to Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1 for use in treatment ofmoderate to severely active rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tomoderate to severely active rheumatoid arthritis, wherein the subjecthas symptoms selected from the group consisting of at least 6 swollenjoints, at least 6 tender joints, and combinations thereof prior totreating, the use comprising administering to the subject about 45 mg,per unit dosage form (e.g., per tablet or capsule) of Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1. In one embodiment, the solid state form is acrystalline hydrate. In one embodiment, the crystalline hydrate is theFreebase Hydrate Form B. In one embodiment, the crystalline hydrate isthe Freebase Hydrate Form C. In one embodiment, the solid state form isa crystalline anhydrate. In one embodiment, the crystalline anhydrate isthe Freebase Anhydrate Form D. In one embodiment, the solid state formis the Tartrate Hydrate. In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is administered orally QD (once daily). In one embodiment,the Compound 1 freebase or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the symptoms result from the progressionof structural damage assessed by radiograph.

In one embodiment, the adult subject receiving the treatment achieves anACR20 response after treatment. In one embodiment, the adult subjectachieves an ACR20 response after treatment for at least twelve weeks(e.g., at week 12 of treating). In another embodiment, the adult subjectreceiving the treatment achieves an ACR50 response after treatment. Inone embodiment, the adult subject achieves an ACR50 response aftertreatment for at least twelve weeks (e.g., at week 12 of treating), orafter at least twenty-four weeks (e.g., at week 24). In anotherembodiment, the adult subject receiving the treatment achieves an ACR70response after treatment. In one embodiment, the adult subject achievesan ACR70 response after treatment for at least twelve weeks (e.g., atweek 12 of treating). In certain embodiments, the adult subject achievesan ACR20 response, an ACR50 response, and/or an ACR70 response followingtreatment for at least twelve weeks (e.g., at week 12 of treating).

In one embodiment, the adult subject receiving the treatment achieves anACR20 response after treatment for at least 8 weeks (e.g., at week 8 oftreating). In another embodiment, the adult subject receiving thetreatment achieves an ACR20 response after treatment for at least 6weeks (e.g., at week 6 of treating). In another embodiment, the adultsubject receiving the treatment achieves an ACR20 response aftertreatment for at least 4 weeks (e.g., at week 4 of treating). In anotherembodiment, the adult subject receiving the treatment achieves an ACR20response after treatment for at least 2 weeks (e.g., at week 2 oftreating).

In one embodiment, the adult subject receiving the treatment achieves anACR50 response after treatment for at least 8 weeks (e.g., at week 8 oftreating). In another embodiment, the adult subject receiving thetreatment achieves an ACR50 response after treatment for at least 6weeks (e.g., at week 6 of treating). In another embodiment, the adultsubject receiving the treatment achieves an ACR50 response aftertreatment for at least 4 weeks (e.g., at week 4 of treating). In anotherembodiment, the adult subject receiving the treatment achieves an ACR50response after treatment for at least 2 weeks (e.g., at week 2 oftreating).

In one embodiment, the adult subject receiving the treatment achieves anACR70 response after treatment for at least 8 weeks (e.g., at week 8 oftreating). In another embodiment, the adult subject receiving thetreatment achieves an ACR70 response after treatment for at least 6weeks (e.g., at week 6 of treating). In another embodiment, the adultsubject receiving the treatment achieves an ACR70 response aftertreatment for at least 4 weeks (e.g., at week 4 of treating).

In one embodiment, the adult subject receiving the treatment achieves achange in DAS28 score after treatment. In one embodiment, the change inDAS score is a decrease in DAS28(CRP) after treatment, as compared tobaseline (i.e., DAS28(CRP) prior to treatment). In one embodiment, theadult subject achieves a decrease in DAS28 score as compared to baselineafter treatment for at least twelve weeks (e.g., at week 12 oftreating). In one embodiment, the adult subject achieves a decrease inDAS28(CRP) as compared to baseline after treatment for at least 12 weeks(e.g., at week 12 of treating). In another embodiment, the adult subjectachieves a decrease in DAS28(CRP) as compared to baseline aftertreatment for at least 8 weeks (e.g., at week 8 of treating). In anotherembodiment, the adult subject achieves a decrease in DAS28(CRP) ascompared to baseline after treatment for at least 6 weeks (e.g., at week6 of treating). In another embodiment, the adult subject achieves adecrease in DAS28(CRP) as compared to baseline after treatment for atleast 4 weeks (e.g., at week 4 of treating). In another embodiment, theadult subject achieves a decrease in DAS28(CRP) as compared to baselineafter treatment for at least 2 weeks (e.g., at week 2 of treating).

In another embodiment, the adult subject receiving the treatmentachieves a low disease activity (LDA) score or clinical remission aftertreatment. In one embodiment, the LDA score or clinical remission ismeasured as a DAS28 score (in particular, DAS28(CRP)) of 3.2 or less. Inanother embodiment, the LDA score or clinical remission is measured as aDAS28(CRP) of less than 2.6. In another embodiment, the LDA score orclinical remission is assessed using Clinical Disease Activity Index(CDAI) criteria. In one embodiment, the adult subject achieves a CDAIscore of 10 or less after treatment. In another embodiment, the adultsubject achieves a CDAI score of 2.8 or less after treatment. In oneembodiment, the adult subject achieves the LDA score or clinicalremission after treatment for at least 12 weeks (e.g., at week 12 oftreating). In one embodiment, the adult subject achieves the LDA scoreor clinical remission after treatment for at least 8 weeks (e.g., atweek 8 of treating). In one embodiment, the adult subject achieves theLDA score or clinical remission after treatment for at least 6 weeks(e.g., at week 6 of treating). In one embodiment, the adult subjectachieves the LDA score or clinical remission after treatment for atleast 4 weeks (e.g., at week 4 of treating). In one embodiment, theadult subject achieves the LDA score or clinical remission aftertreatment for at least 2 weeks (e.g., at week 2 of treating).

In one embodiment, the adult subject receiving the treatment achieves achange in mean modified Total Sharp Score (mTSS). In one embodiment, theadult subject receiving the treatment achieves a change in mTSS aftertreatment for at least twelve weeks (e.g., at week 12 of treating), orafter treatment for at least twenty-four weeks (e.g., at week 24 oftreating). In one embodiment, mTSS may be determined by scoring x-raysof the hand/wrist and feet joints for erosions and joint spacenarrowing. The erosion score and narrowing score are added to determinethe total score.

In one embodiment, the adult subject receiving the treatment achieves achange in HAQ-DI score. In one embodiment, the adult subject receivingthe treatment achieves a change in HAQ-DI score after treatment for atleast twelve weeks (e.g., at week 12 of treating).

In one embodiment, the adult subject receiving the treatment achieves achange in Short Form 36 (SF-36) physical component score (PCS). In oneembodiment, the adult subject receiving the treatment achieves a changein SF-36 PCS after treatment for at least twelve weeks (e.g., at week 12of treating). SF-36 is a 36 item participant questionnaire withquestions relating to participant health and daily activities.

In one embodiment, the adult subject receiving the treatment achieves aclinical remission (CR). In one embodiment, the adult subject receivingthe treatment achieves a CR after treatment for at least twelve weeks(e.g., at week 12 of treating). In one embodiment, CR is determinedbased on DAS28 C-Reactive Protein (DAS28(CRP)) response rate. In oneembodiment, CR is a DAS28(CRP) score of less than 2.6.

In one embodiment, the adult subject receiving the treatment achieves achange in functional assessment of chronic illness therapy (FACIT-F). Inone embodiment, the adult subject receiving the treatment achieves achange in FACIT-F after treatment for at least twelve weeks (e.g., atweek 12 of treating). FACIT-F is a participant questionnaire with 13indexes rated on a 5 point scale. The indexes relate to theparticipant's level of fatigue during the past seven days.

In one embodiment, the adult subject receiving the treatment achieves achange in work instability score for rheumatoid arthritis (RA-WIS). Inone embodiment, the adult subject receiving the treatment achieves achange in RA-WIS after treatment for at least twelve weeks (e.g., atweek 12 of treating). RA-WIS is a participant questionnaire containing23 questions relating to the participant's functioning in their workenvironment.

In one embodiment, the adult subject receiving the treatment achieves achange in morning stiffness severity. In one embodiment, the adultsubject receiving the treatment achieves a change in morning stiffnessseverity after treatment for at least twelve weeks (e.g., at week 12 oftreating). Morning stiffness severity is determined by the Patient'sAssessment of Severity and Duration of Morning Stiffness questionnaire.

In one embodiment, the method or use comprises administering to thesubject about 7.5 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 (freebase), or a pharmaceutically acceptablesalt thereof or a solid state form of Compound 1 in an amount sufficientto deliver to the subject about 7.5 mg, per unit dosage form (e.g., pertablet or capsule), of Compound 1 freebase equivalent to the subject,wherein the subject achieves an ACR20 response at week 12 of treating.In another embodiment, the subject achieves an ACR20 response at week 8of treating. In another embodiment, the subject achieves an ACR20response at week 6 of treating. In another embodiment, the subjectachieves an ACR20 response at week 4 of treating. In another embodiment,the subject achieves an ACR20 response at week 2 of treating. In oneembodiment, the method or use comprises administering to the subjectabout 7.5 mg, per unit dosage form (e.g., per tablet or capsule), ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1 in an amount sufficient to deliver tothe subject about 7.5 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subjectachieves an ACR50 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 8 oftreating. In another embodiment, the subject achieves an ACR50 responseat week 6 of treating. In another embodiment, the subject achieves anACR50 response at week 4 of treating. In one embodiment, the method oruse comprises administering to the subject about 7.5 mg, per unit dosageform (e.g., per tablet or capsule), of Compound 1 (freebase), or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 7.5mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent, wherein the subject achieves an ACR70 response atweek 12 of treating. In one embodiment, the method or use comprisesadministering to the subject about 7.5 mg, per unit dosage form (e.g.,per tablet or capsule), of Compound 1 (freebase), or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 freebase equivalent,wherein the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 12 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 8 oftreating. In another embodiment, the subject achieves a decrease inDAS28(CRP) as compared to baseline at week 6 of treating. In anotherembodiment, the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 4 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 2 oftreating. In one embodiment, the method or use comprises administeringabout 7.5 mg, per unit dosage form (e.g., per tablet or capsule), of thesolid state form to the subject. In one embodiment, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or the solidstate form is in a once daily extended release formulation. In oneembodiment, the solid state form is a crystalline hydrate. In oneembodiment, the crystalline hydrate is the Freebase Hydrate Form B. Inone embodiment, the crystalline hydrate is the Freebase Hydrate Form C.In one embodiment, the solid state form is a crystalline anhydrate. Inone embodiment, the crystalline anhydrate is the Freebase Anhydrate FormD. In one embodiment, the solid state form is the Tartrate Hydrate.

In one embodiment, the method or use comprises administering to thesubject about 15 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 (freebase), or a pharmaceutically acceptable salt thereofor a solid state form of Compound 1 in an amount sufficient to deliverto the subject about 15 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subjectachieves an ACR20 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR20 response at week 8 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 6 of treating. In another embodiment, the subject achieves anACR20 response at week 4 of treating. In another embodiment, the subjectachieves an ACR20 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 15 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 15 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject achieves an ACR50response at week 12 of treating. In another embodiment, the subjectachieves an ACR50 response at week 8 of treating. In another embodiment,the subject achieves an ACR50 response at week 6 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 4 oftreating. In one embodiment, the method or use comprises administeringto the subject about 15 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 (freebase), or a pharmaceutically acceptablesalt thereof or a solid state form of Compound 1 in an amount sufficientto deliver to the subject about 15 mg, per unit dosage form (e.g., pertablet or capsule), of Compound 1 freebase equivalent, wherein thesubject achieves an ACR70 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR70 response at week 8 oftreating. In another embodiment, the subject achieves an ACR70 responseat week 6 of treating. In one embodiment, the method or use comprisesadministering to the subject about 15 mg, per unit dosage form (e.g.,per tablet or capsule), of Compound 1 (freebase), or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 in an amountsufficient to deliver to the subject about 15 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 freebase equivalent,wherein the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 12 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 8 oftreating. In another embodiment, the subject achieves a decrease inDAS28(CRP) as compared to baseline at week 6 of treating. In anotherembodiment, the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 4 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 2 oftreating. In one embodiment, the method or use comprises administeringabout 15 mg, per unit dosage form (e.g., per tablet or capsule), of thesolid state form to the subject. In one embodiment, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or the solidstate form is in a once daily extended release formulation. In oneembodiment, the solid state form is a crystalline hydrate. In oneembodiment, the crystalline hydrate is the Freebase Hydrate Form B. Inone embodiment, the crystalline hydrate is the Freebase Hydrate Form C.In one embodiment, the solid state form is a crystalline anhydrate. Inone embodiment, the crystalline anhydrate is the Freebase Anhydrate FormD. In one embodiment, the solid state form is the Tartrate Hydrate.

In one embodiment, the method or use comprises administering to thesubject about 24 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 (freebase), or a pharmaceutically acceptable salt thereofor a solid state form of Compound 1 in an amount sufficient to deliverto the subject about 24 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subjectachieves an ACR20 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR20 response at week 8 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 6 of treating. In another embodiment, the subject achieves anACR20 response at week 4 of treating. In another embodiment, the subjectachieves an ACR20 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 24 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 24 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject achieves an ACR50response at week 12 of treating. In another embodiment, the subjectachieves an ACR50 response at week 8 of treating. In another embodiment,the subject achieves an ACR50 response at week 6 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 4 oftreating. In one embodiment, the method or use comprises administeringto the subject about 24 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 (freebase), or a pharmaceutically acceptablesalt thereof or a solid state form of Compound 1 in an amount sufficientto deliver to the subject about 24 mg, per unit dosage form (e.g., pertablet or capsule), of Compound 1 freebase equivalent, wherein thesubject achieves an ACR70 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR70 response at week 8 oftreating. In another embodiment, the subject achieves an ACR70 responseat week 6 of treating. In one embodiment, the method or use comprisesadministering to the subject about 24 mg, per unit dosage form (e.g.,per tablet or capsule), of Compound 1 (freebase), or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 in an amountsufficient to deliver to the subject about 24 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 freebase equivalent,wherein the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 12 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 8 oftreating. In another embodiment, the subject achieves a decrease inDAS28(CRP) as compared to baseline at week 6 of treating. In anotherembodiment, the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 4 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 2 oftreating. In one embodiment, the method or use comprises administeringabout 24 mg, per unit dosage form (e.g., per tablet or capsule), of thesolid state form to the subject. In one embodiment, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or the solidstate form is in a once daily extended release formulation. In oneembodiment, the solid state form is a crystalline hydrate. In oneembodiment, the crystalline hydrate is the Freebase Hydrate Form B. Inone embodiment, the crystalline hydrate is the Freebase Hydrate Form C.In one embodiment, the solid state form is a crystalline anhydrate. Inone embodiment, the crystalline anhydrate is the Freebase Anhydrate FormD. In one embodiment, the solid state form is the Tartrate Hydrate.

In one embodiment, the method or use comprises administering to thesubject about 30 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 (freebase), or a pharmaceutically acceptable salt thereofor a solid state form of Compound 1 in an amount sufficient to deliverto the subject about 30 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subjectachieves an ACR20 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR20 response at week 8 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 6 of treating. In another embodiment, the subject achieves anACR20 response at week 4 of treating. In another embodiment, the subjectachieves an ACR20 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 30 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject achieves an ACR50response at week 12 of treating. In another embodiment, the subjectachieves an ACR50 response at week 8 of treating. In another embodiment,the subject achieves an ACR50 response at week 6 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 4 oftreating. In another embodiment, the subject achieves an ACR50 responseat week 2 of treating. In one embodiment, the method or use comprisesadministering to the subject about 30 mg, per unit dosage form (e.g.,per tablet or capsule), of Compound 1 (freebase), or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 in an amountsufficient to deliver to the subject about 30 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 freebase equivalent,wherein the subject achieves an ACR70 response at week 12 of treating.In another embodiment, the subject achieves an ACR70 response at week 8of treating. In one embodiment, the method or use comprisesadministering to the subject about 30 mg, per unit dosage form (e.g.,per tablet or capsule), of Compound 1 (freebase), or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 in an amountsufficient to deliver to the subject about 30 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 freebase equivalent,wherein the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 12 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 8 oftreating. In another embodiment, the subject achieves a decrease inDAS28(CRP) as compared to baseline at week 6 of treating. In anotherembodiment, the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 4 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 2 oftreating. In one embodiment, the method or use comprises administeringabout 30 mg, per unit dosage form (e.g., per tablet or capsule), of thesolid state form to the subject. In one embodiment, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or the solidstate form is in a once daily extended release formulation. In oneembodiment, the solid state form is a crystalline hydrate. In oneembodiment, the crystalline hydrate is the Freebase Hydrate Form B. Inone embodiment, the crystalline hydrate is the Freebase Hydrate Form C.In one embodiment, the solid state form is a crystalline anhydrate. Inone embodiment, the crystalline anhydrate is the Freebase Anhydrate FormD. In one embodiment, the solid state form is the Tartrate Hydrate.

In one embodiment, the method or use comprises administering to thesubject about 45 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 (freebase), or a pharmaceutically acceptable salt thereofor a solid state form of Compound 1 in an amount sufficient to deliverto the subject about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subjectachieves an ACR20 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR20 response at week 8 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 6 of treating. In another embodiment, the subject achieves anACR20 response at week 4 of treating. In another embodiment, the subjectachieves an ACR20 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 45 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 45 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject achieves an ACR50response at week 12 of treating. In another embodiment, the subjectachieves an ACR50 response at week 8 of treating. In another embodiment,the subject achieves an ACR50 response at week 6 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 4 oftreating. In one embodiment, the method or use comprises administeringto the subject about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 (freebase), or a pharmaceutically acceptablesalt thereof or a solid state form of Compound 1 in an amount sufficientto deliver to the subject about 45 mg, per unit dosage form (e.g., pertablet or capsule), of Compound 1 freebase equivalent, wherein thesubject achieves an ACR70 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR70 response at week 8 oftreating. In another embodiment, the subject achieves an ACR70 responseat week 6 of treating. In another embodiment, the subject achieves anACR70 response at week 4 of treating. In one embodiment, the method oruse comprises administering to the subject about 45 mg, per unit dosageform (e.g., per tablet or capsule), of Compound 1 (freebase), or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 45mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent, wherein the subject achieves a decrease inDAS28(CRP) as compared to baseline at week 12 of treating. In anotherembodiment, the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 8 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 6 oftreating. In another embodiment, the subject achieves a decrease inDAS28(CRP) as compared to baseline at week 4 of treating. In anotherembodiment, the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 2 of treating. In one embodiment, the method or usecomprises administering about 45 mg, per unit dosage form (e.g., pertablet or capsule), of the solid state form to the subject. In oneembodiment, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the solid state form is in a once daily extended releaseformulation. In one embodiment, the solid state form is a crystallinehydrate. In one embodiment, the crystalline hydrate is the FreebaseHydrate Form B. In one embodiment, the crystalline hydrate is theFreebase Hydrate Form C. In one embodiment, the solid state form is acrystalline anhydrate. In one embodiment, the crystalline anhydrate isthe Freebase Anhydrate Form D. In one embodiment, the solid state formis the Tartrate Hydrate.

In another embodiment, the adult subject is a subject who has had aninadequate response or intolerance to one or more disease-modifyingantirheumatic drugs (DMARDs). In one embodiment, the DMARD is aconventional synthetic DMARD (csDMARD). In another embodiment, the DMARDis a biologic DMARD (bDMARD). Examples of csDMARDs include, but are notlimited to, methotrexate (MTX), sulfasalazine, hydroxychloroquine,chloroquine, leflunomide, and azathioprine. Examples of bDMARDs include,but are not limited to, tocilizumab such as ACTEMRA™, etanercept such asp75TNFR1gG (ENBREL™ brand etanercept), adalimumab (such as HUMIRA™ brandadalimumab), and golimumab such as SIMPONI™ (golimumab). In oneembodiment, the csDMARD is MTX. In one embodiment, the bDMARD is ananti-TNF biologic. An inadequate response or intolerance to one or moreDMARDs can be measured using any of the indices described herein (e.g.,failure to achieve an ACR20 response). In one embodiment, a subjecthaving an inadequate response to a DMARD is a subject who does notachieve reduced disease activity, does not achieve an improvement inphysical function, exhibits no evidence of stopping disease progression,or who experiences disease relapse after treatment with the DMARD. Inone embodiment, a subject having an inadequate response to a DMARD is asubject who does not achieve an ACR20 response after treatment with theDMARD. In one embodiment, a subject having an inadequate tolerance(intolerance) to a DMARD is a subject who experiences toxicity orcomplicating co-morbidities after treatment with the DMARD.

In one embodiment, the adult subject is a subject who has had aninadequate response to stable methotrexate therapy. In one embodiment,the adult subject received methotrexate therapy for at least threemonths prior to treatment. In another embodiment, the adult subjectreceived a stable dose of methotrexate of about 7.5 to about 25 mg perweek for at least four weeks prior to treatment. In another embodiment,the adult subject is administered a stable dose of methotrexate (e.g.,from about 7.5 to about 25 mg per week) during treatment withCompound 1. In another embodiment, the adult subject received asupplement of folic acid for at least four weeks prior to treatment. Inanother embodiment, the adult subject is administered a supplement offolic acid during treatment.

In one embodiment, the adult subject is a subject who has had aninadequate response or intolerance to at least one anti-TNF therapy.Anti-TNF biologic agents are described elsewhere herein, and include TNFantagonists such as chimeric, humanized or human TNF antibodies,adalimumab (such as HUMIRA™ brand adalimumab), infliximab such as CA2(REMICADE™ brand infliximab), golimumab such as SIMPONI™ (golimumab),certolizumab pegol such as CIMZIA™, tocilizumab such as ACTEMRA™, CDP571, and soluble p55 or p75 TNF receptors, derivatives, thereof,etanercept such as p75TNFR1gG (ENBREL™ brand etanercept) or p55TNFR1gG(lenercept). In one embodiment, the adult subject received methotrexatetherapy for at least three months prior to treatment. In anotherembodiment, the adult subject received a stable dose of methotrexate ofabout 7.5 to about 25 mg per week for at least four weeks prior totreatment. In another embodiment, the adult subject is administered astable dose of methotrexate (e.g., from about 7.5 to about 25 mg perweek) during treatment with Compound 1. In another embodiment, the adultsubject has been treated with at least one anti-TNF biologic agent forat least three months prior to treatment with Compound 1. In anotherembodiment, the adult subject received a supplement of folic acid for atleast four weeks prior to treatment. In another embodiment, the adultsubject is administered a supplement of folic acid during treatment

In certain embodiments, the adult subject, who has had an inadequateresponse or tolerance to one or more DMARDS (including methotrexateand/or an anti-TNF biologic agent), achieves an ACR20 response, an ACR50response, an ACR70 response, and/or a decrease in DAS28(CRP) as comparedto baseline following treatment for at least twelve weeks (e.g., at week12 of treating), and/or following treatment for at least 8 weeks (e.g.,at week 8 of treating), and/or following treatment for at least 6 weeks(e.g., at week 6 of treating), and/or following treatment for at least 4weeks (e.g., at week 4 of treating), and/or following treatment for atleast 2 weeks (e.g., at week 2 of treating).

For instance, in one embodiment, the method or use comprisesadministering to the subject about 7.5 mg, per unit dosage form (e.g.,per tablet or capsule), of Compound 1 (freebase), or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 freebase equivalent,wherein the subject has had an inadequate response or intolerance to oneor more DMARDS, and the subject achieves an ACR20 response at week 12 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 8 of treating. In another embodiment, the subject achieves anACR20 response at week 6 of treating. In another embodiment, the subjectachieves an ACR20 response at week 4 of treating. In another embodiment,the subject achieves an ACR20 response at week 2 of treating. In oneembodiment, the method or use comprises administering to the subjectabout 7.5 mg, per unit dosage form (e.g., per tablet or capsule), ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1 in an amount sufficient to deliver tothe subject about 7.5 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subject has hadan inadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 50 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 8 oftreating. In another embodiment, the subject achieves an ACR50 responseat week 6 of treating. In another embodiment, the subject achieves anACR50 response at week 4 of treating. In one embodiment, the method oruse comprises administering to the subject about 7.5 mg, per unit dosageform (e.g., per tablet or capsule), of Compound 1 (freebase), or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 7.5mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent, wherein the subject has had an inadequate responseor intolerance to one or more DMARDS, and the subject achieves an ACR 70response at week 12 of treating. In one embodiment, the method or usecomprises administering to the subject about 7.5 mg, per unit dosageform (e.g., per tablet or capsule), of Compound 1 (freebase), or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 7.5mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent, wherein the subject has had an inadequate responseor intolerance to one or more DMARDS, and the subject achieves adecrease in DAS28(CRP) as compared to baseline at week 12 of treating.In another embodiment, the subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 8 of treating. In another embodiment, thesubject achieves a decrease in DAS28(CRP) as compared to baseline atweek 6 of treating. In another embodiment, the subject achieves adecrease in DAS28(CRP) as compared to baseline at week 4 of treating. Inanother embodiment, the subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 2 of treating. In one embodiment, themethod or use comprises administering about 7.5 mg, per unit dosage form(e.g., per tablet or capsule), of the solid state form to the subject.In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the solid state form is in a once dailyextended release formulation. In one embodiment, the solid state form isa crystalline hydrate. In one embodiment, the crystalline hydrate is theFreebase Hydrate Form B. In one embodiment, the crystalline hydrate isthe Freebase Hydrate Form C. In one embodiment, the solid state form isa crystalline anhydrate. In one embodiment, the crystalline anhydrate isthe Freebase Anhydrate Form D. In one embodiment, the solid state formis the Tartrate Hydrate.

In one embodiment, the method or use comprises administering to thesubject about 15 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 (freebase), or a pharmaceutically acceptable salt thereofor a solid state form of Compound 1 in an amount sufficient to deliverto the subject about 15 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subject has hadan inadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 20 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR20 response at week 8 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 6 of treating. In another embodiment, the subject achieves anACR20 response at week 4 of treating. In another embodiment, the subjectachieves an ACR20 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 15 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 15 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject has had aninadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 50 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 8 oftreating. In another embodiment, the subject achieves an ACR50 responseat week 6 of treating. In another embodiment, the subject achieves anACR50 response at week 4 of treating. In one embodiment, the method oruse comprises administering to the subject about 15 mg, per unit dosageform (e.g., per tablet or capsule), of Compound 1 (freebase), or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 15mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent, wherein the subject has had an inadequate responseor intolerance to one or more DMARDS, and the subject achieves an ACR 70response at week 12 of treating. In another embodiment, the subjectachieves an ACR70 response at week 8 of treating. In another embodiment,the subject achieves an ACR70 response at week 6 of treating. In oneembodiment, the method or use comprises administering to the subjectabout 15 mg, per unit dosage form (e.g., per tablet or capsule), ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1 in an amount sufficient to deliver tothe subject about 15 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subject has hadan inadequate response or intolerance to one or more DMARDS, and thesubject achieves a decrease in DAS28(CRP) as compared to baseline atweek 12 of treating. In another embodiment, the subject achieves adecrease in DAS28(CRP) as compared to baseline at week 8 of treating. Inanother embodiment, the subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 6 of treating. In another embodiment, thesubject achieves a decrease in DAS28(CRP) as compared to baseline atweek 4 of treating. In another embodiment, the subject achieves adecrease in DAS28(CRP) as compared to baseline at week 2 of treating. Inone embodiment, the method or use comprises administering about 15 mg,per unit dosage form (e.g., per tablet or capsule), of the solid stateform to the subject. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the solid state form is in aonce daily extended release formulation. In one embodiment, the solidstate form is a crystalline hydrate. In one embodiment, the crystallinehydrate is the Freebase Hydrate Form B. In one embodiment, thecrystalline hydrate is the Freebase Hydrate Form C. In one embodiment,the solid state form is a crystalline anhydrate. In one embodiment, thecrystalline anhydrate is the Freebase Anhydrate Form D. In oneembodiment, the solid state form is the Tartrate Hydrate.

In one embodiment, the method or use comprises administering to thesubject about 24 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 (freebase), or a pharmaceutically acceptable salt thereofor a solid state form of Compound 1 in an amount sufficient to deliverto the subject about 24 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subject has hadan inadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 20 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR20 response at week 8 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 6 of treating. In another embodiment, the subject achieves anACR20 response at week 4 of treating. In another embodiment, the subjectachieves an ACR20 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 24 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 24 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject has had aninadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 50 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 8 oftreating. In another embodiment, the subject achieves an ACR50 responseat week 6 of treating. In another embodiment, the subject achieves anACR50 response at week 4 of treating. In another embodiment, the subjectachieves an ACR50 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 24 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 24 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject has had aninadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 70 response at week 12 of treating. In oneembodiment, the method or use comprises administering to the subjectabout 24 mg, per unit dosage form (e.g., per tablet or capsule), ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1 in an amount sufficient to deliver tothe subject about 24 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subject has hadan inadequate response or intolerance to one or more DMARDS, and thesubject achieves a decrease in DAS28(CRP) as compared to baseline atweek 12 of treating. In another embodiment, the subject achieves adecrease in DAS28(CRP) as compared to baseline at week 8 of treating. Inanother embodiment, the subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 6 of treating. In another embodiment, thesubject achieves a decrease in DAS28(CRP) as compared to baseline atweek 4 of treating. In another embodiment, the subject achieves adecrease in DAS28(CRP) as compared to baseline at week 2 of treating. Inone embodiment, the method or use comprises administering about 24 mg,per unit dosage form (e.g., per tablet or capsule), of the solid stateform to the subject. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the solid state form is in aonce daily extended release formulation. In one embodiment, the solidstate form is a crystalline hydrate. In one embodiment, the crystallinehydrate is the Freebase Hydrate Form B. In one embodiment, thecrystalline hydrate is the Freebase Hydrate Form C. In one embodiment,the solid state form is a crystalline anhydrate. In one embodiment, thecrystalline anhydrate is the Freebase Anhydrate Form D. In oneembodiment, the solid state form is the Tartrate Hydrate.

In one embodiment, the method or use comprises administering to thesubject about 30 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 (freebase), or a pharmaceutically acceptable salt thereofor a solid state form of Compound 1 in an amount sufficient to deliverto the subject about 30 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subject has hadan inadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 20 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR20 response at week 8 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 6 of treating. In another embodiment, the subject achieves anACR20 response at week 4 of treating. In another embodiment, the subjectachieves an ACR20 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 30 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject has had aninadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 50 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 8 oftreating. In another embodiment, the subject achieves an ACR50 responseat week 6 of treating. In another embodiment, the subject achieves anACR50 response at week 4 of treating. In another embodiment, the subjectachieves an ACR50 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 30 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject has had aninadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 70 response at week 12 of treating. In oneembodiment, the method or use comprises administering to the subjectabout 30 mg, per unit dosage form (e.g., per tablet or capsule), ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1 in an amount sufficient to deliver tothe subject about 30 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subject has hadan inadequate response or intolerance to one or more DMARDS, and thesubject achieves a decrease in DAS28(CRP) as compared to baseline atweek 12 of treating. In another embodiment, the subject achieves adecrease in DAS28(CRP) as compared to baseline at week 8 of treating. Inanother embodiment, the subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 6 of treating. In another embodiment, thesubject achieves a decrease in DAS28(CRP) as compared to baseline atweek 4 of treating. In another embodiment, the subject achieves adecrease in DAS28(CRP) as compared to baseline at week 2 of treating. Inone embodiment, the method or use comprises administering about 30 mg,per unit dosage form (e.g., per tablet or capsule), of the solid stateform to the subject. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the solid state form is in aonce daily extended release formulation. In one embodiment, the solidstate form is a crystalline hydrate. In one embodiment, the crystallinehydrate is the Freebase Hydrate Form B. In one embodiment, thecrystalline hydrate is the Freebase Hydrate Form C. In one embodiment,the solid state form is a crystalline anhydrate. In one embodiment, thecrystalline anhydrate is the Freebase Anhydrate Form D. In oneembodiment, the solid state form is the Tartrate Hydrate.

In one embodiment, the method or use comprises administering to thesubject about 45 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 (freebase), or a pharmaceutically acceptable salt thereofor a solid state form of Compound 1 in an amount sufficient to deliverto the subject about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subject has hadan inadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 20 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR20 response at week 8 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 6 of treating. In another embodiment, the subject achieves anACR20 response at week 4 of treating. In another embodiment, the subjectachieves an ACR20 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 45 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 45 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject has had aninadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 50 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 8 oftreating. In another embodiment, the subject achieves an ACR50 responseat week 6 of treating. In another embodiment, the subject achieves anACR50 response at week 4 of treating. In one embodiment, the method oruse comprises administering to the subject about 45 mg, per unit dosageform (e.g., per tablet or capsule), of Compound 1 (freebase), or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 45mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent, wherein the subject has had an inadequate responseor intolerance to one or more DMARDS, and the subject achieves an ACR 70response at week 12 of treating. In another embodiment, the subjectachieves an ACR70 response at week 8 of treating. In another embodiment,the subject achieves an ACR70 response at week 6 of treating. In anotherembodiment, the subject achieves an ACR70 response at week 4 oftreating. In one embodiment, the method or use comprises administeringto the subject about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 (freebase), or a pharmaceutically acceptablesalt thereof or a solid state form of Compound 1 in an amount sufficientto deliver to the subject about 45 mg, per unit dosage form (e.g., pertablet or capsule), of Compound 1 freebase equivalent, wherein thesubject has had an inadequate response or intolerance to one or moreDMARDS, and the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 12 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 8 oftreating. In another embodiment, the subject achieves a decrease inDAS28(CRP) as compared to baseline at week 6 of treating. In anotherembodiment, the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 4 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 2 oftreating. In one embodiment, the method or use comprises administeringabout 45 mg, per unit dosage form (e.g., per tablet or capsule), of thesolid state form to the subject. In one embodiment, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or the solidstate form is in a once daily extended release formulation. In oneembodiment, the solid state form is a crystalline hydrate. In oneembodiment, the crystalline hydrate is the Freebase Hydrate Form B. Inone embodiment, the crystalline hydrate is the Freebase Hydrate Form C.In one embodiment, the solid state form is a crystalline anhydrate.

In one embodiment, the crystalline anhydrate is the Freebase AnhydrateForm D. In one embodiment, the solid state form is the Tartrate Hydrate.

In another embodiment, the adult subject is also administered a csDMARDor a bDMARD in a combination therapy, as described hereinafter. Incertain embodiments, the DMARD is MTX. In certain embodiments, the adultsubject receiving the combination therapy achieves an ACR20 response, anACR50 response, an ACR70 response, and/or a decrease in DAS28(CRP) ascompared to baseline following treatment. In particular embodiments, theadult subject receiving the combination therapy achieves an ACR20response, an ACR50 response, an ACR70 response, and/or a decrease inDAS28(CRP) as compared to baseline at week 12 of treating, and/or atweek 8 of treating, and/or at week 6 of treating, and/or at week 4 oftreating, and/or at week 2 of treating. In one embodiment, the adultsubject receiving the combination therapy is administered about 7.5 mg,per unit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 7.5 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent. In one embodiment, theadult subject receiving the combination therapy is administered about 15mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 15 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent. In one embodiment, the adult subjectreceiving the combination therapy is administered about 30 mg, per unitdosage form (e.g., per tablet or capsule), of Compound 1 (freebase), ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 30mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent. In one embodiment, the adult subject receiving thecombination therapy is administered about 45 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 (freebase), or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 45mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent. In one embodiment, the method comprisesadministering about 7.5 mg or about 15 mg or about 30 mg or about 45 mg,per unit dosage form (e.g., per tablet or capsule), of the solid stateform to the subject. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the solid state form is in aonce daily extended release formulation. In one embodiment, the solidstate form is a crystalline hydrate. In one embodiment, the crystallinehydrate is the Freebase Hydrate Form B. In one embodiment, thecrystalline hydrate is the Freebase Hydrate Form C. In one embodiment,the solid state form is a crystalline anhydrate. In one embodiment, thecrystalline anhydrate is the Freebase Anhydrate Form D. In oneembodiment, the solid state form is the Tartrate Hydrate.

In another embodiment, any of the methods of treating an adult subjecthaving moderate to severely active rheumatoid arthritis described hereinmay further comprises alleviating at least one symptom selected from thegroup consisting of bone erosion, cartilage erosion, inflammation, andvascularity. In another embodiment, the arthritis is further treated byalleviating at least one symptom selected from the group consisting ofjoint distortion, swelling, joint deformation, ankyloses on flexion, andseverely impaired movement.

In another embodiment, the present disclosure relates to a method oftreating structural damage associated with rheumatoid arthritis in anadult subject, particularly in a human subject suffering from orsusceptible to structural damage associated with rheumatoid arthritis.The method comprises administering to the subject a therapeuticallyeffective amount of Compound 1 (freebase), or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 (e.g., acrystalline hydrate or a crystalline anhydrate) as described herein,such that the structural damage in the adult subject is inhibited orlessened. In one embodiment, the method comprises administering to thesubject about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, perunit dosage form (e.g., per tablet or capsule), per day of Compound 1(freebase) or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, perunit dosage form (e.g., per tablet or capsule), per day of Compound 1freebase equivalent, such that the structural damage in the adultsubject is inhibited or lessened. In one embodiment, the methodcomprises administering to the subject about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule) of a solid state form of Compound 1, such that the structuraldamage in the adult subject is inhibited or lessened. In one embodiment,the Compound 1 (freebase) or a pharmaceutically acceptable salt thereofor the solid state form of Compound 1 is administered to the subjectorally QD (once daily). In one embodiment, the structural damage isselected from the group consisting of loss of bone and/or cartilage,bone erosion, joint space narrowing as measured by radiography, andcombinations thereof. In one embodiment, the structural damaged isinhibited or lessened when the structural damage is reduced by at least20%, or at least 25%, or at least 30%, or at least 50%. In otherembodiments, structural damage is inhibited or lessened when there is nofurther radiographic progression of the structural damage. In certainembodiments, structural joint damage can be assessed radiographicallyand expressed as change in Total Sharp Score (TSS) and its components,the erosion score and Joint Space Narrowing (JSN) score, for example, atweek 12 compared to baseline. In another aspect, the disclosure relatesto a solid state form (and in particular a crystalline hydrate) ofCompound 1, as described in the present disclosure, for use in treatmentof structural damage associated with rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto rheumatoid arthritis. In one embodiment, the solid state form is acrystalline hydrate. In one embodiment, the crystalline hydrate is theFreebase Hydrate Form B. In one embodiment, the crystalline hydrate is ahemihydrate. In one embodiment, the hemihydrate is Freebase Hydrate FormC. In one embodiment, the solid state form is a crystalline anhydrate.In one embodiment, the crystalline anhydrate is Freebase Anhydrate FormD. In one embodiment, the stolid state form is Tartrate Hydrate. In oneembodiment, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate is in a once daily extendedrelease formulation. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrate isin a once daily extended release formulation, and the formulationdelivers about 7.5 mg or about 15 mg or about 30 mg or about 45 mg perunit dosage form (e.g., per tablet or capsule) of Compound 1 (freebaseequivalent) orally QD (once daily).

In another aspect, the disclosure relates to Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 (e.g., a crystalline hydrate or crystalline anhydrate), asdescribed in the present disclosure for use in treatment of structuraldamage associated with rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tostructural damage associated with rheumatoid arthritis, such that thestructural damage in the adult subject is inhibited or lessened, the usecomprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In one embodiment, thesolid state form is a crystalline hydrate. In one embodiment, thecrystalline hydrate is Freebase Hydrate Form B. In one embodiment, thecrystalline hydrate is a hemihydrate. In one embodiment, the hemihydrateis Freebase Hydrate Form C. In one embodiment, the solid state form is acrystalline anhydrate. In one embodiment, the crystalline anhydrate isFreebase Anhydrate Form D. In one embodiment, the Compound 1 (freebase)or a pharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation. In oneembodiment, the formulation delivers about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg per unit dosage form (e.g., per tablet orcapsule) of Compound 1 (freebase equivalent) or a solid state form ofCompound 1 orally QD (once daily).

In one embodiment, the present disclosure is directed to a method oftreating structural damage associated with rheumatoid arthritis in anadult subject, particularly in a human subject suffering from orsusceptible to structural damage associated with rheumatoid arthritis,the method comprising administering to the subject about 7.5 mg, perunit dosage form (e.g., per tablet or capsule), per day of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 7.5 mg, per unit dosage form (e.g., per tablet orcapsule), per day of Compound 1 freebase equivalent, such that thestructural damage in the adult subject is inhibited or lessened. In oneembodiment, the method comprises administering to the subject about 7.5mg, per unit dosage form (e.g., per tablet or capsule), per day of asolid state form of Compound 1. In another aspect, the disclosurerelates to Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1, for use in treatment ofstructural damage associated with rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto structural damage associated with rheumatoid arthritis, such that thestructural damage in the adult subject is inhibited or lessened, the usecomprising administering to the subject about 7.5 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one embodiment, the solid state form is a crystallinehydrate. In one embodiment, the crystalline hydrate is the FreebaseHydrate Form B. In one embodiment, the crystalline hydrate is theFreebase Hydrate Form C. In one embodiment, the solid state form is acrystalline anhydrate. In one embodiment, the crystalline anhydrate isthe Freebase Anhydrate Form D. In one embodiment, the solid state formis the Tartrate Hydrate. In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is administered orally QD (once daily). In one embodiment,the Compound 1 freebase or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the structural damage is selected fromthe group consisting of loss of bone and/or cartilage, bone erosion,joint space narrowing as measured by radiography, and combinationsthereof.

In one embodiment, the present disclosure is directed to a method oftreating structural damage associated with rheumatoid arthritis in anadult subject, particularly in a human subject suffering from orsusceptible to structural damage associated with rheumatoid arthritis,the method comprising administering to the subject about 15 mg, per unitdosage form (e.g., per tablet or capsule), per day of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 15 mg, per unit dosage form (e.g., per tablet or capsule),per day of Compound 1 freebase equivalent, such that the structuraldamage in the adult subject is inhibited or lessened. In one embodiment,the method comprises administering to the subject about 15 mg, per unitdosage form (e.g., per tablet or capsule), per day of a solid state formof Compound 1. In another aspect, the disclosure relates to Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1, for use in treatment of structural damage associatedwith rheumatoid arthritis in an adult subject, particularly in a humansubject suffering from or susceptible to structural damage associatedwith rheumatoid arthritis, such that the structural damage in the adultsubject is inhibited or lessened, the use comprising administering tothe subject about 15 mg, per unit dosage form (e.g., per tablet orcapsule) of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In one embodiment, thesolid state form is a crystalline hydrate. In one embodiment, thecrystalline hydrate is the Freebase Hydrate Form B. In one embodiment,the crystalline hydrate is the Freebase Hydrate Form C. In oneembodiment, the solid state form is a crystalline anhydrate. In oneembodiment, the crystalline anhydrate is the Freebase Anhydrate Form D.In one embodiment, the solid state form is the Tartrate Hydrate. In oneembodiment, the Compound 1 freebase or a pharmaceutically acceptablesalt thereof or the solid state form of Compound 1 is administeredorally QD (once daily). In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation. In oneembodiment, the structural damage is selected from the group consistingof loss of bone and/or cartilage, bone erosion, joint space narrowing asmeasured by radiography, and combinations thereof.

In one embodiment, the present disclosure is directed to a method oftreating structural damage associated with rheumatoid arthritis in anadult subject, particularly in a human subject suffering from orsusceptible to structural damage associated with rheumatoid arthritis,the method comprising administering to the subject about 30 mg, per unitdosage form (e.g., per tablet or capsule), per day of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg, per unit dosage form (e.g., per tablet or capsule),per day of Compound 1 freebase equivalent, such that the structuraldamage in the adult subject is inhibited or lessened. In one embodiment,the method comprises administering to the subject about 30 mg, per unitdosage form (e.g., per tablet or capsule), per day of a solid state formof Compound 1. In another aspect, the disclosure relates to Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1, for use in treatment of structural damage associatedwith rheumatoid arthritis in an adult subject, particularly in a humansubject suffering from or susceptible to structural damage associatedwith rheumatoid arthritis, such that the structural damage in the adultsubject is inhibited or lessened, the use comprising administering tothe subject about 30 mg, per unit dosage form (e.g., per tablet orcapsule) of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In one embodiment, thesolid state form is a crystalline hydrate. In one embodiment, thecrystalline hydrate is the Freebase Hydrate Form B. In one embodiment,the crystalline hydrate is the Freebase Hydrate Form C. In oneembodiment, the solid state form is a crystalline anhydrate. In oneembodiment, the crystalline anhydrate is the Freebase Anhydrate Form D.In one embodiment, the solid state form is the Tartrate Hydrate. In oneembodiment, the Compound 1 freebase or a pharmaceutically acceptablesalt thereof or the solid state form of Compound 1 is administeredorally QD (once daily). In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation. In oneembodiment, the structural damage is selected from the group consistingof loss of bone and/or cartilage, bone erosion, joint space narrowing asmeasured by radiography, and combinations thereof.

In one embodiment, the present disclosure is directed to a method oftreating structural damage associated with rheumatoid arthritis in anadult subject, particularly in a human subject suffering from orsusceptible to structural damage associated with rheumatoid arthritis,the method comprising administering to the subject about 45 mg, per unitdosage form (e.g., per tablet or capsule), per day of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 45 mg, per unit dosage form (e.g., per tablet or capsule),per day of Compound 1 freebase equivalent, such that the structuraldamage in the adult subject is inhibited or lessened. In one embodiment,the method comprises administering to the subject about 45 mg, per unitdosage form (e.g., per tablet or capsule), per day of a solid state formof Compound 1. In another aspect, the disclosure relates to Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1, for use in treatment of structural damage associatedwith rheumatoid arthritis in an adult subject, particularly in a humansubject suffering from or susceptible to structural damage associatedwith rheumatoid arthritis, such that the structural damage in the adultsubject is inhibited or lessened, the use comprising administering tothe subject 45 mg, per unit dosage form (e.g., per tablet or capsule) ofCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1. In one embodiment, the solid state formis a crystalline hydrate. In one embodiment, the crystalline hydrate isthe Freebase Hydrate Form B. In one embodiment, the crystalline hydrateis the Freebase Hydrate Form C. In one embodiment, the solid state formis a crystalline anhydrate. In one embodiment, the crystalline anhydrateis the Freebase Anhydrate Form D. In one embodiment, the solid stateform is the Tartrate Hydrate. In one embodiment, the Compound 1 freebaseor a pharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is administered orally QD (once daily). In one embodiment,the Compound 1 freebase or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the structural damage is selected fromthe group consisting of loss of bone and/or cartilage, bone erosion,joint space narrowing as measured by radiography, and combinationsthereof.

In another embodiment, the present disclosure is directed to a method ofreducing signs and symptoms of rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tomoderately to severely active rheumatoid arthritis. The method comprisesadministering to the subject a therapeutically effective amount ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1 (e.g., a crystalline hydrate or acrystalline anhydrate) as described herein. In one embodiment, themethod comprises administering to the subject about 7.5 mg or about 15mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tabletor capsule), per day of Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), per day of Compound 1 freebase equivalent. In one embodiment,the method comprises administering to the subject about 7.5 mg or about15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., pertablet or capsule) of a solid state form of Compound 1. In oneembodiment, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the solid state form of Compound 1 is administered tothe subject orally QD (once daily). In another aspect, the disclosurerelates to Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form (and in particular a crystalline hydrate)of Compound 1, as described in the present disclosure, for use inreducing signs and symptoms of rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tomoderate to severely active rheumatoid arthritis, the use comprisingadministering to the subject a therapeutically effective amount ofCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form (and in particular a crystalline hydrate) ofCompound 1. In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation. In oneembodiment, the formulation delivers about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg per unit dosage form (e.g., per tablet orcapsule) of Compound 1 (freebase equivalent) or the solid state form ofCompound 1 to the subject orally QD (once daily). In one embodiment, thesolid state form is a crystalline hydrate. In one embodiment, thecrystalline hydrate is the Freebase Hydrate Form B. In one embodiment,the crystalline hydrate is the Freebase Hydrate Form C. In oneembodiment, the solid state form is a crystalline anhydrate. In oneembodiment, the crystalline anhydrate is the Freebase Anhydrate Form D.In one embodiment, the solid state form is the Tartrate Hydrate.

In one embodiment, the present disclosure is directed to a method ofreducing the signs and symptoms of rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto moderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 7.5 mg, per unit dosageform (e.g., per tablet or capsule), per day of Compound 1 (freebase), ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 7.5mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent. In one embodiment, the method comprisesadministering to the subject about 7.5 mg, per unit dosage form (e.g.,per tablet or capsule), per day of a solid state form of Compound 1. Inanother aspect, the disclosure relates to Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 for use in reducing signs and symptoms of rheumatoidarthritis in an adult subject, particularly in a human subject sufferingfrom or susceptible to moderate to severely active rheumatoid arthritis,the use comprising administering to the subject about 7.5 mg, per unitdosage form (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one embodiment, the solid state form is a crystallinehydrate. In one embodiment, the crystalline hydrate is the FreebaseHydrate Form B. In one embodiment, the crystalline hydrate is ahemihydrate. In one embodiment, the hemihydrate is the Freebase HydrateForm C. In one embodiment, the solid state form is a crystallineanhydrate. In one embodiment, the crystalline anhydrate is the FreebaseAnhydrate Form D. In one embodiment, the solid state form is theTartrate Hydrate. In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is administered orally QD (once daily). In one embodiment,the Compound 1 freebase or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation, and theformulation delivers about 7.5 mg per unit dosage form (e.g., per tabletor capsule) of Compound 1 (freebase equivalent) or the solid state formof Compound 1 orally QD (once daily) to the subject.

In one embodiment, the present disclosure is directed to a method ofreducing the signs and symptoms of rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto moderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 15 mg, per unit dosageform (e.g., per tablet or capsule), per day of Compound 1 (freebase) ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 15mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent. In one embodiment, the method comprisesadministering to the subject about 15 mg, per unit dosage form (e.g.,per tablet or capsule), per day of a solid state form of Compound 1. Inanother aspect, the disclosure relates to Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 for use in reducing signs and symptoms of rheumatoidarthritis in an adult subject, particularly in a human subject sufferingfrom or susceptible to moderate to severely active rheumatoid arthritis,the use comprising administering to the subject, about 15 mg, per unitdosage form (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one embodiment, the solid state form is a crystallinehydrate. In one embodiment, the crystalline hydrate is a hemihydrate. Inone embodiment, the hemihydrate is Freebase Hydrate Form C. In oneembodiment, the crystalline hydrate is the Freebase Hydrate Form B. Inone embodiment, the solid state form is a crystalline anhydrate. In oneembodiment, the crystalline anhydrate is the Freebase Anhydrate Form D.In one embodiment, the solid state form is the Tartrate Hydrate. In oneembodiment, the Compound 1 freebase or the solid state form of Compound1 is administered orally QD (once daily). In one embodiment, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation, and theformulation delivers about 15 mg per unit dosage form (e.g., per tabletor capsule) of Compound 1 (freebase equivalent) or the solid state formof Compound 1 orally QD (once daily) to the subject.

In another embodiment, the present disclosure is directed to a method ofreducing signs and symptoms of rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tomoderately to severely active rheumatoid arthritis. The method comprisesadministering to the subject about 30 mg, per unit dosage form (e.g.,per tablet or capsule), per day of Compound 1 (freebase) or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 30mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent. In one embodiment, the method comprisesadministering to the subject about 30 mg, per unit dosage form (e.g.,per tablet or capsule), per day of a solid state form of Compound 1. Inanother aspect, the disclosure relates to Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 for use in reducing signs and symptoms of rheumatoidarthritis in an adult subject, particularly in a human subject sufferingfrom or susceptible to moderate to severely active rheumatoid arthritis,the use comprising administering to the subject about 30 mg, per unitdosage form (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one embodiment, the solid state form is a crystallinehydrate. In one embodiment, the crystalline hydrate is a hemihydrate. Inone embodiment, the hemihydrate is Freebase Hydrate Form C. In oneembodiment, the crystalline hydrate is the Freebase Hydrate Form B. Inone embodiment, the solid state form is a crystalline anhydrate. In oneembodiment, the crystalline anhydrate is the Freebase Anhydrate Form D.In one embodiment, the solid state form is the Tartrate Hydrate. In oneembodiment, the Compound 1 freebase or a pharmaceutically acceptablesalt thereof or the solid state form of Compound 1 is administeredorally QD (once daily). In one embodiment, the Compound 1 (freebase) orthe crystalline hydrate is in a once daily extended release formulation.In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the solid state form of Compound 1 is in aonce daily extended release formulation, and the formulation deliversabout 30 mg per unit dosage form (e.g., per tablet or capsule) ofCompound 1 (freebase equivalent) or the solid state form of Compound 1orally QD (once daily) to the subject.

In one embodiment, the present disclosure is directed to a method ofreducing the signs and symptoms of rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto moderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 45 mg, per unit dosageform (e.g., per tablet or capsule), per day of Compound 1 (freebase), ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 45mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent. In one embodiment, the method comprisesadministering to the subject about 45 mg, per unit dosage form (e.g.,per tablet or capsule), per day of a solid state form of Compound 1. Inanother aspect, the disclosure relates to Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 for use in reducing signs and symptoms of rheumatoidarthritis in an adult subject, particularly in a human subject sufferingfrom or susceptible to moderate to severely active rheumatoid arthritis,the use comprising administering to the subject about 45 mg, per unitdosage form (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one embodiment, the solid state form is a crystallinehydrate. In one embodiment, the crystalline hydrate is the FreebaseHydrate Form B. In one embodiment, the crystalline hydrate is ahemihydrate. In one embodiment, the hemihydrate is the Freebase HydrateForm C. In one embodiment, the solid state form is a crystallineanhydrate. In one embodiment, the crystalline anhydrate is the FreebaseAnhydrate Form D. In one embodiment, the solid state form is theTartrate Hydrate. In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is administered orally QD (once daily). In one embodiment,the Compound 1 freebase or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation, and theformulation delivers about 45 mg per unit dosage form (e.g., per tabletor capsule) of Compound 1 (freebase equivalent) or the solid state formof Compound 1 orally QD (once daily) to the subject.

In another aspect, the disclosure relates to a solid state form (and inparticular a crystalline hydrate) of Compound 1, as described in thepresent disclosure, for use in reducing signs and symptoms of rheumatoidarthritis in an adult subject, particularly in a human subject sufferingfrom or susceptible to rheumatoid arthritis.

In another embodiment, any of the methods of reducing signs and symptomsof rheumatoid arthritis described herein may further comprisesalleviating at least one symptom selected from the group consisting ofbone erosion, cartilage erosion, inflammation, and vascularity. Inanother embodiment, the arthritis is further treated by alleviating atleast one symptom selected from the group consisting of jointdistortion, swelling, joint deformation, ankyloses on flexion, andseverely impaired movement.

In another embodiment, the Compound 1 freebase or a pharmaceuticallyacceptable salt thereof and/or solid state forms of Compound 1 used inany of the methods set forth herein may be administered to the subjectin a once daily extended release solid oral dosage form. In particular,in one embodiment, the methods comprise once daily administration to thesubject of an extended release (e.g., modified release) solid oraldosage form comprising the Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or the solid state form of Compound 1, and apharmaceutically acceptable polymeric carrier substantially contributingto the modification of the release of the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1. In one aspect, the dosage form sustains release of theCompound 1 freebase or a pharmaceutically acceptable salt thereof or thesolid state form of Compound 1 for from about 4 hours to about 24 hoursfollowing entry of the dosage form into a use environment. In oneembodiment, the dosage form has a release rate of not more than about60% after passage of about 4 hours following entry of the dosage forminto a use environment. The term “entry into a use environment” refersto contact of the dosage form with gastric fluids of the subject to whomit is administered. As used herein, the term “release rate” refers tothe percentage of the active ingredient (e.g., Compound 1 or a solidstate form of Compound 1) in the dosage form that is released in thegiven time period, and under the specified conditions. In oneembodiment, the dosage form comprises about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 (freebase), or a pharmaceutically acceptablesalt thereof or a solid state form of Compound 1 in an amount sufficientto deliver to the subject about 7.5 mg or about 15 mg or about 30 mg orabout 45 mg, per unit dosage form (e.g., per tablet or capsule), per dayof Compound 1 freebase equivalent. In one embodiment, the dosage formcomprises about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, perunit dosage form (e.g., per tablet or capsule), per day of a solid stateform of Compound 1. In one embodiment, the solid state form is FreebaseHydrate Form B. In one embodiment, the solid state form is FreebaseHydrate Form C. In one embodiment, the solid state form is FreebaseAnhydrate Form D. In one embodiment, the solid state form is TartrateHydrate. In one embodiment, the pharmaceutically acceptable polymericcarrier is a release control polymer, as set forth herein.

Thus, in one aspect, the dosage form sustains release of the Compound 1freebase or a pharmaceutically acceptable salt thereof or the solidstate form of Compound 1 for from about 4 hours to about 24 hours. Inone embodiment, the dosage form releases the active ingredient (i.e.,Compound 1 or a solid state form of Compound 1), at a release rate ofnot more than about 25%, or from about 10% to about 25%, or from about15% to about 20%, or about 20% after passage of about 1 hour followingentry into the use environment. In one embodiment, the dosage formreleases the active ingredient at a release rate of not more than about40%, or from about 20% to about 40%, or from about 25% to about 35%after passage of about 2 hours following entry into the use environment.In one embodiment, the dosage form releases the active ingredient at arelease rate of not more than about 60%, or from about 30% to about 60%,or from about 40% to about 60%, or from about 45% to about 55% afterpassage of about 4 hours following entry into the use environment. Inone embodiment, the dosage form releases the active ingredient at arelease rate of not more than about 70% or from about 40% to about 70%,or from about 55% to about 70% after passage of about 6 hours followingentry into the use environment. In one embodiment, the dosage formreleases the active ingredient at a release rate of not more than about80% or from about 55% to about 80%, or from about 60% to about 80% afterpassage of about 6 hours following entry into the use environment. Inone embodiment, the dosage form releases the active ingredient at arelease rate of not more than about 80%, or not less than about 50%, ornot less than about 60%, or not less than about 70%, or not less thanabout 75%, or from about 50% to about 80%, or from about 60% to about80%, or from about 65% to about 80% after passage of about 8 hoursfollowing entry into the use environment. In one embodiment, the dosageform releases the active ingredient at a release rate of not less thanabout 55%, or not less than about 60% or not less than about 70%, or notless than about 80%, or not less than about 85%, or from about 55% toabout 90%, or from about 70% to about 90% after passage of about 10hours following entry into the use environment. In one embodiment, thedosage form releases the active ingredient at a release rate of not lessthan about 65%, or not less than about 70%, or not less than about 80%,or not less than about 90%, or from about 65% to about 99%, or fromabout 80% to about 99%, or from about 90% to about 99% after passage ofabout 16 hours following entry into the use environment. In oneembodiment, the dosage form releases the active ingredient at a releaserate of not less than about 70%, or not less than about 80%, or not lessthan about 90%, or from about 70% to 100%, or from about 80% to 100%after passage of about 20 hours following entry into the useenvironment. In one aspect, the dosage form has a release rate of notmore than about 60% after passage of about 4 hours following entry ofthe dosage form into a use environment, from about 50% to about 80%after passage of about 8 hours following entry of the dosage form into ause environment, from about 55% to about 90% after passage of about 10hours following entry of the dosage form into a use environment, andfrom about 70% to 100% after passage of about 20 hours following entryof the dosage form into a use environment.

In one embodiment, the present disclosure is directed to a method oftreating a condition selected from the group consisting of rheumatoidarthritis, juvenile idiopathic arthritis, Crohn's disease, ulcerativecolitis, psoriasis, plaque psoriasis, nail psoriasis, psoriaticarthritis, ankylosing spondylitis, alopecia areata, hidradenitissuppurativa, atopic dermatitis, and systemic lupus erythematosus, themethod comprising once daily administration to a subject suffering fromor susceptible to the condition, of an extended release solid oraldosage form comprising about 7.5 mg or about 15 mg or about 30 mg orabout 45 mg, per unit dosage form (e.g., per tablet or capsule), ofCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 in an amount sufficient to deliver to thesubject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg,per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent, and a pharmaceutically acceptable polymeric carriersubstantially contributing to the modification of the release of theCompound 1 freebase or a pharmaceutically acceptable salt thereof or thesolid state form of Compound 1, wherein the dosage form sustains releaseof the Compound 1 freebase or a pharmaceutically acceptable salt thereofor the solid state form of Compound 1 for from about 4 to about 24 hoursfollowing entry of the dosage form into a use environment, wherein thedosage form has a release rate of not more than about 60% after passageof about 4 hours following said entry into said use environment. In oneembodiment, the dosage form comprises about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of a solid state form of Compound 1. In one embodiment, thesolid state form is Freebase Hydrate Form B. In one embodiment, thesolid state form is Freebase Hydrate Form C. In one embodiment, thesolid state form is Freebase Anhydrate Form D. In one embodiment, thesolid state form is Tartrate Hydrate. In one embodiment, the dosage formfurther has a release rate of from about 50% to about 80% after passageof about 8 hours following entry of the dosage form into a useenvironment, from about 55% to about 90% after passage of about 10 hoursfollowing entry of the dosage form into a use environment, and/or fromabout 70% to 100% after passage of about 20 hours following entry of thedosage form into a use environment.

In another aspect, the disclosure is directed to an extended releasesolid oral dosage form comprising Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 for use in treating a condition selected from the groupconsisting of rheumatoid arthritis, juvenile idiopathic arthritis,Crohn's disease, ulcerative colitis, psoriasis, plaque psoriasis, nailpsoriasis, psoriatic arthritis, ankylosing spondylitis, alopecia areata,hidradenitis suppurativa, atopic dermatitis, and systemic lupuserythematosus, the use comprising once daily administration to a subjectsuffering from or susceptible to the condition, of the extended releasesolid oral dosage form, wherein the solid dosage form comprises about7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase, or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 7.5mg, or about 15 mg, or about 30 mg, or about 45 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 freebase equivalent, and apharmaceutically acceptable polymeric carrier substantially contributingto the modification of the release of the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1, wherein the dosage form sustains release of the Compound 1freebase or a pharmaceutically acceptable salt thereof or the solidstate form of Compound 1 for from about 4 to about 24 hours followingentry of the dosage form into a use environment, wherein the dosage formhas a release rate of not more than about 60% after passage of about 4hours following said entry into said use environment. In one embodiment,the dosage form comprises about 7.5 mg or about 15 mg or about 30 mg orabout 45 mg, per unit dosage form (e.g., per tablet or capsule), of asolid state form of Compound 1. In one embodiment, the solid state formis Freebase Hydrate Form B. In one embodiment, the solid state form isFreebase Hydrate Form C. In one embodiment, the solid state form isFreebase Anhydrate Form D. In one embodiment, the solid state form isTartrate Hydrate. In one embodiment, the dosage form further has arelease rate of from about 50% to about 80% after passage of about 8hours following entry of the dosage form into a use environment, fromabout 55% to about 90% after passage of about 10 hours following entryof the dosage form into a use environment, and/or from about 70% to 100%after passage of about 20 hours following entry of the dosage form intoa use environment.

In another embodiment, the disclosure is directed to a method oftreating an adult subject having moderate to severely active rheumatoidarthritis, the method comprising once daily administration to thesubject, particularly a human subject suffering from or susceptible torheumatoid arthritis, of an extended release solid oral dosage formcomprising about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg,per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1 in an amount sufficient to deliver to the subjectabout 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg, per unitdosage form (e.g., per tablet or capsule), of Compound 1 freebaseequivalent, and a pharmaceutically acceptable polymeric carriersubstantially contributing to the modification of the release of theCompound 1 freebase or a pharmaceutically acceptable salt thereof or thesolid state form of Compound 1, wherein the dosage form sustains releaseof the Compound 1 freebase or a pharmaceutically acceptable salt thereofor the solid state form of Compound 1 for from about 4 to about 24 hoursfollowing entry of the dosage form into a use environment, wherein thedosage form has a release rate of not more than about 60% after passageof about 4 hours following said entry into said use environment. In oneembodiment, the dosage form comprises about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of a solid state form of Compound 1. In one embodiment, thesolid state form is Freebase Hydrate Form B. In one embodiment, thesolid state form is Freebase Hydrate Form C. In one embodiment, thesolid state form is Freebase Anhydrate Form D. In one embodiment, thesolid state form is Tartrate Hydrate. In one embodiment, the dosage formfurther has a release rate of from about 50% to about 80% after passageof about 8 hours following entry of the dosage form into a useenvironment, from about 55% to about 90% after passage of about 10 hoursfollowing entry of the dosage form into a use environment, and/or fromabout 70% to 100% after passage of about 20 hours following entry of thedosage form into a use environment. In one embodiment, the subject hassymptoms selected from the group consisting of at least 6 swollenjoints, at least 6 tender joints, and combinations thereof prior totreating.

In another aspect, the disclosure is directed to an extended releasesolid oral dosage form comprising Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 for use in treating an adult subject having moderate toseverely active rheumatoid arthritis, the use comprising once dailyadministration to the subject, particularly a subject suffering from orsusceptible to moderately to severely active rheumatoid arthritis, ofthe extended release solid oral dosage form, wherein the solid dosageform comprises about 7.5 mg or about 15 mg or about 30 mg or about 45mg, per unit dosage form (e.g., per tablet or capsule) of Compound 1freebase or a pharmaceutically acceptable salt thereof, or a solid stateform of Compound 1 in an amount sufficient to deliver to the subjectabout 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg, per unitdosage form (e.g., per tablet or capsule), of Compound 1 freebaseequivalent, and a pharmaceutically acceptable polymeric carriersubstantially contributing to the modification of the release of theCompound 1 freebase or a pharmaceutically acceptable salt thereof or thesolid state form of Compound 1, wherein the dosage form sustains releaseof the Compound 1 freebase or a pharmaceutically acceptable salt thereofor the solid state form of Compound 1 for from about 4 to about 24 hoursfollowing entry of the dosage form into a use environment, wherein thedosage form has a release rate of not more than about 60% after passageof about 4 hours following said entry into said use environment. In oneembodiment, the dosage form comprises about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of a solid state form of Compound 1. In one embodiment, thesolid state form is Freebase Hydrate Form B. In one embodiment, thesolid state form is Freebase Hydrate Form C. In one embodiment, thesolid state form is Freebase Anhydrate Form D. In one embodiment, thesolid state form is Tartrate Hydrate. In one embodiment, the dosage formfurther has a release rate of from about 50% to about 80% after passageof about 8 hours following entry of the dosage form into a useenvironment, from about 55% to about 90% after passage of about 10 hoursfollowing entry of the dosage form into a use environment, and/or fromabout 70% to 100% after passage of about 20 hours following entry of thedosage form into a use environment. In one embodiment, the subject hassymptoms selected from the group consisting of at least 6 swollenjoints, at least 6 tender joints, and combinations thereof prior totreating.

In one embodiment, the disclosure is directed to a method of treatingstructural damage associated with rheumatoid arthritis in an adultsubject, the method comprising once daily administration to the subject,particularly a human subject suffering from or susceptible to rheumatoidarthritis, of an extended release solid oral dosage form comprisingabout 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg, per unitdosage form (e.g., per tablet or capsule), of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 7.5mg, or about 15 mg, or about 30 mg, or about 45 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 freebase or apharmaceutically acceptable salt thereof equivalent, and apharmaceutically acceptable polymeric carrier substantially contributingto the modification of the release of the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1, wherein the dosage form sustains release of the Compound 1freebase or a pharmaceutically acceptable salt thereof or the solidstate form of Compound 1 for from about 4 to about 24 hours followingentry of the dosage form into a use environment, wherein the dosage formhas a release rate of not more than about 60% after passage of about 4hours following said entry into said use environment. In one embodiment,the dosage form comprises about 7.5 mg or about 15 mg or about 30 mg orabout 45 mg, per unit dosage form (e.g., per tablet or capsule), of asolid state form of Compound 1. In one embodiment, the solid state formis Freebase Hydrate Form B. In one embodiment, the solid state form isFreebase Hydrate Form C. In one embodiment, the solid state form isFreebase Anhydrate Form D. In one embodiment, the solid state form isTartrate Hydrate. In one embodiment, the dosage form further has arelease rate of from about 50% to about 80% after passage of about 8hours following entry of the dosage form into a use environment, fromabout 55% to about 90% after passage of about 10 hours following entryof the dosage form into a use environment, and/or from about 70% to 100%after passage of about 20 hours following entry of the dosage form intoa use environment.

In another aspect, the disclosure is directed to an extended releasesolid oral dosage form comprising Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 for use in treating structural damage associated withrheumatoid arthritis in an adult subject, the use comprising once dailyadministration to the subject, particularly a subject suffering from orsusceptible to structural damage associated with rheumatoid arthritis,of the extended release solid oral dosage form, wherein the solid dosageform comprises about 7.5 mg or about 15 mg or about 30 mg or about 45mg, per unit dosage form (e.g., per tablet or capsule) of Compound 1freebase, or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1 in an amount sufficient to deliver to the subjectabout 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg, per unitdosage form (e.g., per tablet or capsule), of Compound 1 freebaseequivalent, and a pharmaceutically acceptable polymeric carriersubstantially contributing to the modification of the release of theCompound 1 freebase or a pharmaceutically acceptable salt thereof or thesolid state form of Compound 1, wherein the dosage form sustains releaseof the Compound 1 freebase or a pharmaceutically acceptable salt thereofor the solid state form of Compound 1 for from about 4 to about 24 hoursfollowing entry of the dosage form into a use environment, wherein thedosage form has a release rate of not more than about 60% after passageof about 4 hours following said entry into said use environment. In oneembodiment, the dosage form comprises about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of a solid state form of Compound 1. In one embodiment, thesolid state form is Freebase Hydrate Form B. In one embodiment, thesolid state form is Freebase Hydrate Form C. In one embodiment, thesolid state form is Freebase Anhydrate Form D. In one embodiment, thesolid state form is Tartrate Hydrate. In one embodiment, the dosage formfurther has a release rate of from about 50% to about 80% after passageof about 8 hours following entry of the dosage form into a useenvironment, from about 55% to about 90% after passage of about 10 hoursfollowing entry of the dosage form into a use environment, and/or fromabout 70% to 100% after passage of about 20 hours following entry of thedosage form into a use environment.

In one embodiment, the disclosure is directed to a method of reducingsigns and symptoms of rheumatoid arthritis in an adult subject, themethod comprising once daily administration to the subject, particularlya human subject suffering from or susceptible to moderately to severelyactive rheumatoid arthritis, of an extended release solid oral dosageform comprising about 7.5 mg or about 15 mg or about 30 mg or about 45mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1 in an amount sufficient to deliver to the subjectabout 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unitdosage form (e.g., per tablet or capsule), of Compound 1 freebaseequivalent, and a pharmaceutically acceptable polymeric carriersubstantially contributing to the modification of the release of theCompound 1 freebase or a pharmaceutically acceptable salt thereof or thesolid state form of Compound 1, wherein the dosage form sustains releaseof the Compound 1 freebase or a pharmaceutically acceptable salt thereofor the solid state form of Compound 1 for from about 4 to about 24 hoursfollowing entry of the dosage form into a use environment, wherein thedosage form has a release rate of not more than about 60% after passageof about 4 hours following said entry into said use environment. In oneembodiment, the dosage form comprises about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of a solid state form of Compound 1. In one embodiment, thesolid state form is Freebase Hydrate Form B. In one embodiment, thesolid state form is Freebase Hydrate Form C. In one embodiment, thesolid state form is Freebase Anhydrate Form D. In one embodiment, thesolid state form is Tartrate Hydrate. In one embodiment, the dosage formfurther has a release rate of from about 50% to about 80% after passageof about 8 hours following entry of the dosage form into a useenvironment, from about 55% to about 90% after passage of about 10 hoursfollowing entry of the dosage form into a use environment, and/or fromabout 70% to 100% after passage of about 20 hours following entry of thedosage form into a use environment.

In another aspect, the disclosure is directed to an extended releasesolid oral dosage form comprising Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 for use in reducing signs and symptoms associated withrheumatoid arthritis in an adult subject, the use comprising once dailyadministration to the subject, particularly a subject suffering from orsusceptible to rheumatoid arthritis, of the extended release solid oraldosage form, wherein the solid dosage form comprises about 7.5 mg orabout 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g.,per tablet or capsule) of Compound 1 freebase, or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg, or about 15 mg, orabout 30 mg, or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, and a pharmaceuticallyacceptable polymeric carrier substantially contributing to themodification of the release of the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1, wherein the dosage form sustains release of the Compound 1freebase or a pharmaceutically acceptable salt thereof or the solidstate form of Compound 1 for from about 4 to about 24 hours followingentry of the dosage form into a use environment, wherein the dosage formhas a release rate of not more than about 60% after passage of about 4hours following said entry into said use environment. In one embodiment,the dosage form comprises about 7.5 mg or about 15 mg or about 30 mg orabout 45 mg, per unit dosage form (e.g., per tablet or capsule), of asolid state form of Compound 1. In one embodiment, the solid state formis Freebase Hydrate Form B. In one embodiment, the solid state form isFreebase Hydrate Form C. In one embodiment, the solid state form isFreebase Anhydrate Form D. In one embodiment, the solid state form isTartrate Hydrate. In one embodiment, the dosage form further has arelease rate of from about 50% to about 80% after passage of about 8hours following entry of the dosage form into a use environment, fromabout 55% to about 90% after passage of about 10 hours following entryof the dosage form into a use environment, and/or from about 70% to 100%after passage of about 20 hours following entry of the dosage form intoa use environment.

In the foregoing methods, in one embodiment, the pharmaceuticallyacceptable polymeric carrier comprises a release control polymer. In oneembodiment, the release control polymer is hydroxypropylmethylcellulose. In one embodiment, the dosage form comprises a pH modifier.In one embodiment, the pH modifier is tartaric acid. In one embodiment,the dosage form comprises from about 10 w/w % to about 35 w/w % tartaricacid. In one embodiment, the dosage form comprises about 10 w/w %tartaric acid. In one embodiment, the dosage form comprises about 20 w/w% tartaric acid. In one embodiment, the dosage form comprises about 30w/w % tartaric acid.

In another embodiment the methods of the present disclosure furthercomprise administering Compound 1 or a solid state form thereof for atleast 8 weeks. In another embodiment, the methods of the presentdisclosure comprise administering Compound 1 or a solid state formthereof for at least 12 weeks.

In another embodiment, the present disclosure relates to the use of asolid state form of Compound 1 for treating a condition as described inthe various embodiments of the present disclosure.

In another embodiment, the present disclosure relates to a solid stateform of Compound 1 for use in treatment of a condition as described inthe various embodiments of the present disclosure.

V. COMBINATION THERAPY AND FIXED-DOSE COMBINATIONS

The present disclosure further relates to (i) methods of treatment anduses as previously described that further comprise the administration ofone or more additional therapeutic agents (i.e., combination therapies),and (ii) pharmaceutical compositions as previously described thatfurther comprise one or more additional therapeutic agents (i.e.,fixed-dose combinations). When administered to a subject in combinationwith one or more additional therapeutic agents, the solid state form ofCompound 1 and the additional therapeutic agent(s) can be administeredas separate dosage forms or as a single dosage form comprising the solidstate form of Compound 1 and the additional therapeutic agent(s). Ifadministered as a separate dosage form, the additional therapeutic agentmay be administered either simultaneously with, or sequentially with,the dosage form comprising the solid state form of Compound 1.

For example, the solid state forms of the present disclosure may beadministered in a pharmaceutically acceptable form either alone or incombination with one or more additional agents that modulate a mammalianimmune system or with anti-inflammatory agents. These agents may includebut are not limited to cyclosporin A (e.g., SANDIMMUNE® or NEORAL®,rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin,mycophenolate (e.g., CELLCEPT®), azathioprine (e.g., IMURAN®),daclizumab (e.g., ZENAPAX®), OKT3 (e.g., ORTHOCLONE®), AtGam, aspirin,acetaminophen, aminosalicylate, ciprofloxacin, corticosteroid,metronidazole, probiotic, tacrolimus, ibuprofen, naproxen, piroxicam,and anti-inflammatory steroids (e.g., prednisolone or dexamethasone). Incertain embodiments, the one or more additional agents are selected fromthe group consisting of aspirin, acetaminophen, aminosalicylate,ciprofloxacin, corticosteroid, cyclosporine, metronidazole, probiotic,tacrolimus, ibuprofen, naproxen, piroxicam, prednisolone, dexamethasone,anti-inflammatory steroid, methotrexate, chloroquine, azathioprine,hydroxychloroquine, penicillamine, sulfasalazine, leflunomide,tocilizumab, anakinra, abatacept, certolizumab pegol, golimumab,vedolizumab, natalizumab, ustekinumab, rituximab, efalizumab, belimumab,etanercept, infliximab, adalimumab, and immune modulator (e.g.,activator) for CD4+CD25+ T_(reg) cells.

Non-limiting examples of therapeutic agents for rheumatoid arthritiswith which a compound of the invention can be combined include thefollowing: cytokine suppressive anti-inflammatory drug(s) (CSAIDs);antibodies to or antagonists of other human cytokines or growth factors,for example, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8,IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF,and PDGF. Compounds of the invention can be combined with antibodies tocell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30,CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligandsincluding CD154 (gp39 or CD40L). Combinations of therapeutic agents mayinterfere at different points in the autoimmune and subsequentinflammatory cascade. Such examples may include TNF antagonists likechimeric, humanized or human TNF antibodies, adalimumab (such as HUMIRA™brand adalimumab), infliximab such as CA2 (REMICADE™ brand infliximab),golimumab such as SIMPONI™ (golimumab), certolizumab pegol such asCIMZIA™, tocilizumab such as ACTEMRA™, CDP 571, and soluble p55 or p75TNF receptors, derivatives, thereof, etanercept such as p75TNFR1gG(ENBREL™ brand etanercept) or p55TNFR1gG (lenercept), and also TNFαconverting enzyme (TACE) inhibitors; similarly IL-1 inhibitors(Interleukin-1-converting enzyme inhibitors, IL-IRA etc.) may beeffective for the same reason. Other combinations include Interleukin11.

The solid state form may also be combined with nonbiologic DMARDS orother agents, such as methotrexate, 6-mercaptopurine, azathioprinesulphasalazine, mesalazine, olsalazine chloroquinine/hydroxychloroquine,penicillamine, aurothiomalate (intramuscular and oral), azathioprine,colchicine, corticosteroids (oral, inhaled and local injection), beta-2adrenoreceptor agonists (salbutamol, terbutaline, salmeterol), xanthines(theophylline, aminophylline), cromoglycate, nedocromil, ketotifen,ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolatemofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroidssuch as prednisolone, phosphodiesterase inhibitors, adenosine agonists,antithrombotic agents, complement inhibitors, adrenergic agents, agentswhich interfere with signalling by proinflammatory cytokines such asIL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1β convertingenzyme inhibitors, T-cell signalling inhibitors such as kinaseinhibitors, metalloproteinase inhibitors, sulfasalazine, and6-mercaptopurines. The solid state form may also be combined withmethotrexate.

Non-limiting examples of therapeutic agents for inflammatory boweldisease (IBD) with which the solid state form can be combined mayinclude (but are not limited to) the following: budesonide; epidermalgrowth factor; corticosteroids; cyclosporin, sulfasalazine;aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole;lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide;antioxidants; thromboxane inhibitors; IL-1 receptor antagonists;anti-IL-1β monoclonal antibodies; anti-IL-6 monoclonal antibodies;growth factors; elastase inhibitors; pyridinyl-imidazole compounds;antibodies to or antagonists of other human cytokines or growth factors,for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16,IL-23, EMAP-II, GM-CSF, FGF, and PDGF; cell surface molecules such asCD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or theirligands; methotrexate; cyclosporine; FK506; rapamycin; mycophenolatemofetil; leflunomide; NSAIDs, for example, ibuprofen; corticosteroidssuch as prednisolone; phosphodiesterase inhibitors; adenosine agonists;antithrombotic agents; complement inhibitors; adrenergic agents; agentswhich interfere with signalling by proinflammatory cytokines such asTNFα or IL-1 (e.g., NIK, IKK, or MAP kinase inhibitors); IL-1βconverting enzyme inhibitors; TNFα converting enzyme inhibitors; T-cellsignalling inhibitors such as kinase inhibitors; metalloproteinaseinhibitors; sulfasalazine; azathioprine; 6-mercaptopurines; angiotensinconverting enzyme inhibitors; soluble cytokine receptors and derivativesthereof (e.g. soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII,sIL-6R) and anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-11, IL-13and TGFβ). The solid state form may also be combined with methotrexate.

Examples of therapeutic agents for Crohn's disease with which the solidstate form can be combined include the following: TNF antagonists, forexample, anti-TNF antibodies, adalimumab (such as HUMIRA™ brandadalimumab), infliximab such as CA2 (REMICADE™ brand infliximab),certolizumab pegol such as CIMZIA™, golimumab such as SIMPONI™(golimumab), CDP 571, TNFR-Ig constructs, etanercept such as p75TNFRIgG(ENBREL™ brand etanercept) and lenercept such as p55TNFRIgG (Lenercept™)inhibitors and PDE4 inhibitors.

The solid state form can be combined with corticosteroids, for example,budesonide and dexamethasone; sulfasalazine, 5-aminosalicylic acid;olsalazine; and agents which interfere with synthesis or action ofproinflammatory cytokines such as IL-1, for example, IL-1β convertingenzyme inhibitors and IL-1ra; T cell signaling inhibitors, for example,tyrosine kinase inhibitors; 6-mercaptopurine; IL-11; mesalamine;prednisone; azathioprine; mercaptopurine; methylprednisolone sodiumsuccinate; diphenoxylate/atrop sulfate; loperamide hydrochloride;methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water;hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide;metronidazole; thimerosal/boric acid; cholestyramine/sucrose;ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidinehydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen;promethazine hydrochloride; sodium phosphate;sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphenenapsylate; hydrocortisone; multivitamins; balsalazide disodium; codeinephosphate/apap; colesevelam HCl; cyanocobalamin; folic acid;levofloxacin; methylprednisolone; natalizumab and interferon-gamma.

Non-limiting examples of therapeutic agents for multiple sclerosis (MS)with which the solid state form can be combined include the following:corticosteroids; prednisolone; methylprednisolone; azathioprine;cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine;tizanidine; interferon-β1a (AVONEX®; Biogen); interferon-β1b(BETASERON®; Chiron/Berlex); interferon α-n3) (InterferonSciences/Fujimoto), interferon-α (Alfa Wassermann/J&J), interferonβ1A-IF (Serono/Inhale Therapeutics), Peginterferon α 2b(Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; TevaPharmaceutical Industries, Inc.); hyperbaric oxygen; intravenousimmunoglobulin; cladribine; antibodies to or antagonists of other humancytokines or growth factors and their receptors, for example, TNF, LT,IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II,GM-CSF, FGF, and PDGF. A compound of the invention can be combined withantibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19,CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or theirligands. The solid state form may also be combined with agents such asmethotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil,leflunomide, an S1P1 agonist, NSAIDs, for example, ibuprofen,corticosteroids such as prednisolone, phosphodiesterase inhibitors,adenosine agonists, antithrombotic agents, complement inhibitors,adrenergic agents, agents which interfere with signalling byproinflammatory cytokines such as TNFα or IL-1 (e.g., NIK, IKK, p38 orMAP kinase inhibitors), IL-1β converting enzyme inhibitors, TACEinhibitors, T-cell signaling inhibitors such as kinase inhibitors,metalloproteinase inhibitors, sulfasalazine, azathioprine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g., soluble p55 or p75 TNFreceptors, sIL-1RI, sIL-1RII, sIL-6R) and anti-inflammatory cytokines(e.g. IL-4, IL-10, IL-13 and TGFβ). Examples of therapeutic agents formultiple sclerosis in which a compound of the invention can be combinedto include interferon-β, for example, IFNβ1a and IFNβ1b; copaxone,corticosteroids, caspase inhibitors, for example inhibitors ofcaspase-1, IL-1 inhibitors, TNF inhibitors, and antibodies to CD40ligand and CD80.

The solid state form may also be combined with agents, such asalemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliprodenhydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol,α-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptorantagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulatedmitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidoneallotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2,tiplimotide, VLA-4 antagonists (for example, TR-14035, VLA4 Ultrahaler,Antegran-ELAN/Biogen), interferon gamma antagonists and IL-4 agonists.

Non-limiting examples of therapeutic agents for ankylosing spondylitis(AS) with which the solid state form can be combined include thefollowing: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam,indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine,methotrexate, azathioprine, minocycline, prednisone, and anti-TNFantibodies, adalimumab (such as HUMIRA™ brand adalimumab), infliximabsuch as CA2 (REMICADE™ brand infliximab), CDP 571, TNFR-Ig constructs,etanercept such as p75TNFRIgG (ENBREL™ brand etanercept) and lenerceptsuch as p55TNFRIgG (LENERCEPT™).

Non-limiting examples of therapeutic agents for psoriasis (Ps, such asmoderate to severe plaque psoriasis) with which the solid state form canbe combined include the following: calcipotriene, clobetasol propionate,triamcinolone acetonide, halobetasol propionate, tazarotene,methotrexate, fluocinonide, betamethasone diprop augmented, fluocinoloneacetonide, acitretin, tar shampoo, betamethasone valerate, mometasonefuroate, ketoconazole, pramoxine/fluocinolone, hydrocortisone valerate,flurandrenolide, urea, betamethasone, clobetasol propionate/emoll,fluticasone propionate, azithromycin, hydrocortisone, moisturizingformula, folic acid, desonide, pimecrolimus, coal tar, diflorasonediacetate, etanercept folate, lactic acid, methoxsalen, hc/bismuthsubgal/znox/resor, methylprednisolone acetate, prednisone, sunscreen,halcinonide, salicylic acid, anthralin, clocortolone pivalate, coalextract, coal tar/salicylic acid, coal tar/salicylic acid/sulfur,desoximetasone, diazepam, emollient, fluocinonide/emollient, mineraloil/castor oil/na lact, mineral oil/peanut oil, petroleum/isopropylmyristate, psoralen, salicylic acid, soap/tribromsalan, thimerosal/boricacid, celecoxib, infliximab, cyclosporine, alefacept, efalizumab,tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874,ustekinumab, and adalimumab (such as HUMIRA™ brand adalimumab).

Non-limiting examples of therapeutic agents for psoriatic arthritis(PsA) with which the solid state form can be combined include thefollowing: methotrexate, etanercept, rofecoxib, celecoxib, folic acid,sulfasalazine, naproxen, leflunomide, methylprednisolone acetate,indomethacin, hydroxychloroquine sulfate, prednisone, sulindac,betamethasone diprop augmented, infliximab, methotrexate, folate,triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam,diclofenac sodium, ketoprofen, meloxicam, methylprednisolone,nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenacsodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodiumthiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium,sulfadiazine, thioguanine, valdecoxib, alefacept, adalimumab (such asHUMIRA™ brand adalimumab), and efalizumab.

Examples of therapeutic agents for SLE (Lupus) with which the solidstate form can be combined include the following: NSAIDS, for example,diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2inhibitors, for example, celecoxib, rofecoxib, valdecoxib;anti-malarials, for example, hydroxychloroquine; steroids, for example,prednisone, prednisolone, budesonide, dexamethasone; cytotoxics, forexample, azathioprine, cyclophosphamide, mycophenolate mofetil,methotrexate; inhibitors of PDE4 or purine synthesis inhibitor, forexample CELLCEPT®. The solid state form may also be combined with agentssuch as sulfasalazine, 5-aminosalicylic acid, olsalazine, IMURAN® andagents which interfere with synthesis, production or action ofproinflammatory cytokines such as IL-1, for example, caspase inhibitorslike IL-1β converting enzyme inhibitors and IL-1ra. The solid state formmay also be used with T cell signaling inhibitors, for example, tyrosinekinase inhibitors; or molecules that target T cell activation molecules,for example, CTLA-4-IgG or anti-B7 family antibodies, anti-PD-1 familyantibodies. The solid state form can be combined with IL-11 oranti-cytokine antibodies, for example, fontolizumab (anti-IFNgantibody), or anti-receptor receptor antibodies, for example, anti-IL-6receptor antibody and antibodies to B-cell surface molecules. The solidstate form may also be used with LJP 394 (abetimus), agents that depleteor inactivate B-cells, for example, Rituximab (anti-CD20 antibody),lymphostat-B (anti-BlyS antibody), TNF antagonists, for example,anti-TNF antibodies, adalimumab (such as HUMIRA™ brand adalimumab),infliximab such as CA2 (REMICADE™ brand infliximab), CDP 571, TNFR-Igconstructs, etanercept such as p75TNFRIgG (ENBREL™ brand etanercept) andlenercept such as p55TNFRIgG (LENERCEPT™).

The solid state form may also be combined with an immune modulator forCD4+CD25+ T_(reg) cells. T_(reg) cells are essential for maintainingnormal immune homeostasis. In patients with autoimmune diseases, reducednumbers or functional impairment of T_(reg) cells has been observed,leading to loss of this finely-tuned mechanism. A humanized agonisticmonoclonal antibody, BT-061, binds to a unique epitope of human CD4, andinduces T_(reg)-specific signaling events that lead to their functionalactivation. Pre-clinical data using isolated T_(reg) cells andrheumatoid arthritis synovial fluid indicate that BT-061 leads tosuppression of CD4+ and CD8+T effector cell proliferation, reduction ofthe expression of pro-inflammatory cytokines, and increase in theproduction of the anti-inflammatory cytokine TGFβ. Thus similar immunemodulators for CD4+CD25+ T_(reg) cells can also be co-administered witha compound of the invention for treating any of the inflammatorydisease/disorder, or an autoimmune disease/disorder described herein,including but not limited to rheumatoid arthritis, Crohn's disease,ankylosing spondylitis, psoriatic arthritis, psoriasis, ulcerativecolitis, systemic lupus erythematosus, lupus nephritis, diabeticnephropathy, dry eye syndrome, Sjogren's syndrome, alopecia areata,vitiligo, or atopic dermatitis. In certain embodiments, the combinationtreats rheumatoid arthritis, Crohn's disease, psoriasis, or psoriaticarthritis, including moderately to severely active rheumatoid arthritis,Crohn's disease, psoriasis, or psoriatic arthritis. In certainembodiments, the rheumatoid arthritis, Crohn's disease, psoriasis, orpsoriatic arthritis patient being treated has inadequately responded toor has discontinued therapy due to loss of response to or intolerance toa first line therapy (such as a DMARD, including methotrexate) or ananti-TNFα therapy.

In certain embodiments, the immune modulator has one or more (or all) ofthe following properties: (1) activates a subset of CD4+ T cellscomprising CD4+CD25+ regulatory T cells (T_(reg)), or CD4+CD25+ T_(reg)cells; (2) binds only to a special epitope of the human CD4 antigen(such as the IgG-like C2 type 1 domain of CD4), which said epitope ofhuman CD4 may be bound by a mouse IgG1 anti-CD4 monoclonal antibody B-F5or a humanized version thereof, such as the BT-061 hB-F5 antibodytregalizumab as described in U.S. Pat. No. 7,452,981 (incorporatedherein by reference, including all sequences of the VH and VL chainsdisclosed therein); (3) provides an activation signal to naturallyoccurring T_(reg) cells but does not activate conventional T cells(e.g., CD4+ T cells that are not activated in (1), CD8+ cytotoxic Tcells, etc.); and (4) is not a depleting anti-CD4 antibody that depletesCD4+ T cells, and/or does not appreciably trigger ADCC or CDC.

VI. PHARMACEUTICAL COMPOSITIONS

The present disclosure further relates, in part, to compositionscomprising Compound 1 or a pharmaceutically acceptable salt thereof, orone or more solid state forms of Compound 1. Although the solid stateform may be administered alone or in the form of a pharmaceuticalcomposition, administration generally will be in the form of apharmaceutical composition. In some embodiments, the compositioncomprises Compound 1 or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 in association with a pharmaceuticallyacceptable carrier. The preferred composition depends on the method ofadministration, and typically comprises one or more conventionalpharmaceutically acceptable carriers, adjuvants, and/or vehicles(together referred to as “excipients”). Such compositions can beformulated for various routes of systemic or local delivery for example,by oral administration, topical administration, transmucosaladministration, rectal administration, intravaginal administration, oradministration by subcutaneous, intrathecal, intravenous, intramuscular,intraperitoneal, intranasal, intraocular or intraventricular injection.

Solid dosage forms for oral administration include, for example,capsules, tablets, pills, powders, and granules. In such solid dosageforms, the compounds or salts are ordinarily combined with one or moreexcipients. If administered per os, the compounds or salts can be mixedwith, for example, lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets cancontain a controlled-release formulation, as can be provided in, forexample, a dispersion of the compound or salt in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage formsalso can comprise pH modifiers, such as sodium citrate; magnesium orcalcium carbonate or bicarbonate; tartaric acid, fumaric acid, citricacid, succinic acid, malic acid, and phosphoric acid and combinationsthereof. Tablets and pills additionally can be prepared with entericcoatings.

Liquid dosage forms for oral administration include, for example,pharmaceutically acceptable emulsions (including both oil-in-water andwater-in-oil emulsions), solutions (including both aqueous andnon-aqueous solutions), suspensions (including both aqueous andnon-aqueous suspensions), syrups, and elixirs containing inert diluentscommonly used in the art (e.g., water). Such compositions also cancomprise, for example, wetting, emulsifying, suspending, sweeting andflavoring agents.

Parenteral administration includes subcutaneous injections, intravenousinjections, intramuscular injections, intrasternal injections, andinfusion. Injectable preparations (e.g., sterile injectable aqueous oroleaginous suspensions) can be formulated according to the known artusing suitable dispersing, wetting agents, and/or suspending agents.Acceptable vehicles and solvents include, for example, water,1,3-butanediol, Ringer's solution, isotonic sodium chloride solution,bland fixed oils (e.g., synthetic mono- or diglycerides), fatty acids(e.g., oleic acid), dimethyl acetamide, surfactants (e.g., ionic andnon-ionic detergents), and/or polyethylene glycols.

Formulations for parenteral administration may, for example, be preparedfrom sterile powders or granules having one or more of the excipientsmentioned for use in the formulations for oral administration. Acompound or salt of the invention can be dissolved in water,polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseedoil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/orvarious pH modifiers. The pH may be adjusted, if necessary, with asuitable acid, base, or pH modifier.

Suppositories for rectal administration can be prepared by, for example,mixing a compound or salt of the invention with a suitable nonirritatingexcipient that is solid at ordinary temperatures, but liquid at therectal temperature, and will therefore melt in the rectum to release thedrug. Suitable excipients include, for example, cocoa butter; syntheticmono-, di-, or triglycerides, fatty acids, and/or polyethylene glycols.

Compound 1 or the solid state forms of the present disclosure can beformulated for administration topically to the skin or mucosa, i.e.,dermally or transdermally. Such administration can include the use,e.g., of transdermal patches or iontophoresis devices.

Besides those representative dosage forms described above,pharmaceutically acceptable excipients and carriers are generally knownto those skilled in the art and are thus included in the instantinvention. Formulation of drugs is generally discussed in, for example,Hoover, J., Remington's Pharmaceutical Sciences (Mack Publishing Co.,1975) and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems(Lippincott Williams & Wilkins, 2005).

Depending upon the route and frequency of administration, thepharmaceutical compositions of the present invention can contain, forexample, from about 0.1 percent by weight to about 99 percent or more byweight of the active ingredient. The amount of active ingredientcontained in the dosage unit composition employed for adult humantreatment generally can range, for example, from about 0.01 mg to about3000 mg. For the therapeutic uses described in this application, theamount of active ingredient contained in the dosage unit compositiongenerally will be in the range, for example, from about 0.1 mg to about1000 mg. In one embodiment, the amount of active ingredient contained inthe dosage unit composition is in a range from about 1 mg to about 500mg. In another embodiment, the amount of active ingredient contained inthe dosage unit composition is in a range from about 1 mg to about 250mg. In another embodiment, the amount of active ingredient contained inthe dosage unit composition is in a range from about 1 mg to about 100mg. In another embodiment, the amount of active ingredient contained inthe dosage unit composition is in a range from about 1 mg to about 50mg. In another embodiment, the amount of active ingredient contained inthe dosage unit composition is in a range from about 1 mg to about 45mg. In another embodiment, the amount of active ingredient contained inthe dosage unit composition is in a range from about 1 mg to about 30mg. In another embodiment, the amount of active ingredient contained inthe dosage unit composition is in a range from about 1 mg to about 25mg. In another embodiment, the amount of active ingredient contained inthe dosage unit composition is in a range from about 1 mg to about 24mg. In another embodiment, the amount of active ingredient contained inthe dosage unit composition is in a range from about 1 mg to about 15mg. In another embodiment, the amount of active ingredient contained inthe dosage unit composition is in a range from about 1 mg to about 10mg. In another embodiment, the amount of active ingredient contained inthe dosage unit composition is in a range from about 1 mg to about 7.5mg. In another embodiment, the amount of active ingredient contained inthe dosage unit composition is in a range from about 10 mg to about 20mg. In another embodiment, the amount of active ingredient contained inthe dosage unit composition is in a range from about 20 mg to about 30mg. In another embodiment, the amount of active ingredient contained inthe dosage unit composition is in a range from about 30 mg to about 40mg. In another embodiment, the amount of active ingredient contained inthe dosage unit composition is in a range from about 7.5 mg to about 45mg. In another embodiment, the amount of active ingredient contained inthe dosage unit composition is in a range from about 15 mg to about 30mg. In another embodiment, the amount of active ingredient contained inthe dosage unit composition is about 3 mg. In another embodiment, theamount of active ingredient contained in the dosage unit composition isabout 6 mg. In another embodiment, the amount of active ingredientcontained in the dosage unit composition is about 7.5 mg. In anotherembodiment, the amount of active ingredient contained in the dosage unitcomposition is about 12 mg. In another embodiment, the amount of activeingredient contained in the dosage unit composition is about 15 mg. Inanother embodiment, the amount of active ingredient contained in thedosage unit composition is about 18 mg. In another embodiment, theamount of active ingredient contained in the dosage unit composition isabout 24 mg. In another embodiment, the amount of active ingredientcontained in the dosage unit composition is about 30 mg. In anotherembodiment, the amount of active ingredient contained in the dosage unitcomposition is about 36 mg. In another embodiment, the amount of activeingredient contained in the dosage unit composition is about 45 mg.

In one embodiment, the active ingredient contained in the dosage unitcomposition is Compound 1, or a pharmaceutically acceptable saltthereof. In one embodiment, the target or label amount of activeingredient (e.g., Compound 1) provided for inclusion in the compositionsof the present disclosure refers to the amount of Compound 1 freebase.For instance, as discussed herein, Compound 1 may be prepared in severalsolid state forms including Amorphous Freebase, crystalline solvates andhydrates (e.g., Freebase Solvate Form A, Freebase Hydrate Form B),crystalline hemihydrates (e.g., Freebase Hydrate Form C), crystallineanhydrate (e.g., Freebase Anhydrate Form D), crystalline tartrate (e.g.,Tartrate Hydrate), crystalline hydrochloride (e.g., HydrochlorideSolvate Form AA, Hydrochloride Solvate Form BB, Hydrochloride SolvateForm CC), and crystalline L-maleate (e.g., L-Maleate Form AAA, L-MaleateForm BBB, L-Maleate Form CCC). It should be understood that inembodiments, where the dosage unit composition comprises, e.g., asolvate, hydrate, hemihydrate, tartrate, hydrochloride, or L-maleate ofCompound 1, the amount of solvate, hydrate, hemihydrate, tartrate,hydrochloride, or L-maleate of Compound 1 present in the dosage unitcomposition may be slightly higher than the target amount of Compound 1(active ingredient), and preferably will be present in the dosage unitcomposition in an amount sufficient to deliver the target amount ofCompound 1 freebase equivalent to a subject. For example, if the targetamount of Compound 1 (active ingredient) in a dosage unit composition is15 mg, a dosage unit composition comprising, for example, FreebaseHydrate Form C, may comprise the Freebase Hydrate Form C in an amountsufficient to deliver 15 mg of the Compound 1 freebase equivalent.

In one embodiment, the pharmaceutical composition is a tablet dosageform. In one aspect, the tablet is coated with a pharmaceuticallyacceptable polymer.

In one embodiment, tablet is a controlled-release formulation, such asan extended release tablet dosage form (also referred to herein as amodified release or sustained release formulation). Such formulationspermit the sustained release of the active ingredient over an extendedperiod of time, as compared to immediate release solid dosage forms,which permit the release of most or all of the active ingredient over ashort period of time (e.g., typically around 60 minutes or less). In oneaspect, the tablet comprises an active ingredient and at least oneadditive selected from the group consisting of a release controlpolymer, a filler, a glidant, a lubricant (e.g., for use in compactingthe granules), a pH modifier, a surfactant, and combinations thereof. Inone aspect, the tablet comprises an active ingredient, a release controlpolymer, a filler, a glidant, and a lubricant. In one aspect, the tabletcomprises an active ingredient, a release control polymer, a filler, aglidant, a lubricant, and a pH modifier.

In certain embodiments, the release control polymer will be ahydrophilic polymer. Examples of suitable release control polymersinclude, but are not limited to a cellulose derivative with a viscosityof between 1000 and 150,000 mPA-s, hydroxypropylmethyl cellulose (e.g.,Hypromellose 2208 or controlled release grades of hydroxypropylmethylcellulose, including the E, F, and K series), copolymers of acrylic acidcrosslinked with a polyalkenyl polyether (e.g., Carbopol® polymers),hydroxypropyl cellulose, hydroxyethyl cellulose, non-ionic homopolymersof ethylene oxide (e.g., Polyox™), water soluble natural gums ofpolysaccharides (e.g., xanthan gum, alginate, locust bean gum, etc.),crosslinked starch, polyvinyl acetates, polyvinylpyrrolidone, mixturesof polyvinyl acetates and polyvinyl pyrrolidone, and combinationsthereof. In one embodiment, the release control polymer is selected fromthe group consisting of hydroxypropylmethyl cellulose, copolymers ofacrylic acid crosslinked with a polyalkenyl polyether (e.g., Carbopol®polymers), and combinations thereof. Examples of suitable fillers(“bulking agents”) include, but are not limited to, microcrystallinecellulose (e.g., Avicel® PH 101; Avicel® PH 102), mannitol (e.g.,Pearlitol® 100 SD or Pearlitol® 200 SD), lactose, sucrose, sorbitol, andthe like. In one embodiment, the filler is selected from the groupconsisting of microcrystalline cellulose, mannitol, and combinationsthereof. Examples of suitable glidants include, but are not limited to,silicone dioxide (e.g., colloidal silicon dioxide), calcium silicate,magnesium silicate, talc, and combinations thereof. In one embodiment,the glidant is colloidal silicone dioxide. Examples of suitablelubricants include, but are not limited to, polyethylene glycol (e.g.,having a molecular weight of from 1000 to 6000), magnesium stearate,calcium stearate, sodium stearyl fumarate, talc, and the like. In oneembodiment, the lubricant is magnesium stearate. Examples of suitable pHmodifiers include, but are not limited to, organic acids, such astartaric acid, citric acid, succinic acid, fumaric acid; sodium citrate;magnesium or calcium carbonate or bicarbonate; and combinations thereof.In one embodiment, the pH modifier is tartaric acid. Examples ofsuitable surfactants include sodium lauryl sulfate.

In one embodiment, the pharmaceutical composition comprises from about10 w/w % to about 35 w/w % of a pH modifier, and in particular, tartaricacid, fumaric acid, citric acid, succinic acid, malic acid, orcombinations thereof. In other embodiments, the formulation comprisesfrom about 20 w/w % to about 35 w/w %, or from about 20 w/w % to about30 w/w %, or from about 20 w/w % to about 25 w/w %, or about 10 w/w %,about 15 w/w. %, about 20 w/w %, about 25 w/w % or about 30 w/w % pHmodifier. In one embodiment, the pH modifier is tartaric acid.

As discussed herein, sustained peak plasma concentrations cantheoretically be achieved by means of sustained release matrix systems.However, when such systems are made of hydrophilic polymers, such asHPMC, they seldom provide pH independent drug release of pH-dependentsoluble drugs, and they are normally incapable of attaining zero-orderrelease except for practically insoluble drugs. Unexpectedly, is has nowbeen discovered that when a pH modifier, such as tartaric acid, fumaricacid, citric acid, succinic acid, malic acid, or combinations thereof,is used in a hydrophilic sustained release matrix system, it allowsCompound 1 or a pharmaceutically acceptable salt or solid state formthereof to be released at a steady rate regardless of the pH of theenvironment. In an unexpected finding, it was discovered that as atablet containing the hydrophilic polymer matrix system erodes, Compound1 reacts with the HPMC, creating a thicker gel layer which slows therelease of Compound 1 from the tablet. The resulting gel layer providesan environment suitable for Compound 1 to dissolve.

Thus, in one embodiment, the pharmaceutical composition of the presentdisclosure exhibits a pH-independent release of the active ingredient(Compound 1). Advantageously, it has been discovered that includingorganic acids, such as a tartaric acid, in the composition as a pHmodifier improves the release profile, and results in a pH independentrelease of the active ingredient. Without wishing to be bound to anyparticular theory, it is believed that the pH modifier and hydrophilicpolymer create a microenvironment in which the active ingredientdissolves, and then is released. The release from the microenvironmentoccurs at approximately the same rate, regardless of pH. This isparticularly advantageous, since the pH of the gastrointestinal tractmay vary significantly from the stomach (e.g., pH of about 1.5-3), tothe duodenum (e.g., pH of about 4-5), to the lower part of the smallintestines (e.g., pH of about 6.5-7.5).

Thus, in one embodiment, the pharmaceutical composition is an extendedrelease formulation comprising Compound 1, or a pharmaceuticallyacceptable salt or solid state form thereof, a hydrophilic polymer, anda pH modifier, wherein the hydrophilic polymer, in contact with water,forms a gel layer that provides an environment suitable for Compound 1,or a pharmaceutically acceptable salt or solid state form thereof, todissolve. In some embodiments, the environment suitable for Compound 1,or a pharmaceutically acceptable salt or solid state form thereof, todissolve has a pH equal to or less than about 3.8 at 37° C. In some suchembodiments, the environment has a pH of from about 1.5 to about 3.7, orfrom about 2.0 to about 3.7, or from about 2.5 to about 3.6, or fromabout 3.0 to about 3.6, or from about 3.0 to about 3.5.

In one such embodiment, the environment suitable for Compound 1, or apharmaceutically acceptable salt or solid state form thereof, todissolve is as set forth above, and the extended release formulationcomprises from about 10 w/w % to about 35 w/w % of a pH modifier, and inparticular, tartaric acid, fumaric acid, citric acid, succinic acid,malic acid, or combinations thereof. In other embodiments, theformulation comprises from about 20 w/w % to about 35 w/w %, or fromabout 20 w/w % to about 30 w/w %, or from about 20 w/w % to about 25 w/w%, or about 10 w/w %, about 15 w/w %, about 20 w/w %, about 25 w/w % orabout 30 w/w % pH modifier. In any of these embodiments, the pH modifiermay be selected from the group consisting of tartaric acid, fumaricacid, citric acid, succinic acid, malic acid, and combinations thereof.In one such embodiment, the pH modifier is selected from the groupconsisting of tartaric acid, fumaric acid, citric acid, succinic acid,and combinations thereof. In one such embodiment, the pH modifier isselected from the group consisting of tartaric acid and fumaric acid. Inone embodiment, the pH modifier is tartaric acid. In one embodiment, thepH modifier is fumaric acid or citric acid. The weight % tartaric acidset forth herein is by weight of the uncoated composition (e.g.,uncoated tablet). In any of the foregoing embodiments, the hydrophilicpolymer may be a cellulose derivative with a viscosity of between 1000and 150,000 mPA-s. In one embodiment, the hydrophilic polymer isselected from the group consisting of hydroxypropylmethyl cellulose,hydroxyethyl cellulose, and mixtures or combinations thereof. In oneembodiment, the hydrophilic polymer is hydroxypropylmethyl cellulose. Inone embodiment, the hydrophilic polymer is hydroxypropylmethyl celluloseGrade E, F, or K. In one embodiment, the hydrophilic polymer isHypromellose 2208.

In one embodiment, the tablet is a compressed and/or milled tablet. Forexample, in some embodiments, the tablet is formed by blending thecomposition components (e.g., including the active ingredient and atleast one pharmaceutically acceptable carrier). The composition can thenbe either directly compressed, or one or more of the compositioncomponents can be granulated prior to compression. In one embodiment,milling is performed using a mill fitted with any suitable size screen(e.g., a fitted with a screen size of from about 600 to about 1400 μm orabout 610 μm or about 1397 μm). Compression can be done in a tabletpress, such as in a steel die between two moving punches.

In other embodiments, the compressed and/or milled tablet is formulatedusing a wet granulation process. Use of wet granulation helps reduceand/or eliminate sticking that may occur when compression without wetgranulation (e.g., direct compression) is used to formulate the tablets.In one embodiment, the wet granulation process may include the followingsteps: (a) combining the active ingredient (e.g., Compound 1 or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1) and at least a portion of one additional compositioncomponent to form a dry granulation mixture; (b) contacting the drygranulation mixture with a granulation fluid to form a wet granulationmixture; (c) drying the wet granulation mixture to form a granulatedmaterial; (d) milling the granulated material to form a milledgranulated material; (e) combining the milled granulation material withthe remaining composition components; and (f) compressing thecomposition into the solid dosage unit (e.g., a tablet).

In step (a) of this process, the active ingredient may be combined with,for example, a portion of the release control polymer (e.g., HPMC), aportion of the filler (e.g., microcrystalline cellulose, such as Avicel®PH101), or both a portion of the release control polymer and a portionof the filler to form the dry granulation mixture. Any suitable portionof the release control polymer may be used in step (a). In oneembodiment, from about 5 to 10 wt. % or from about 6 to 8 wt. % of thetotal amount of the release control polymer in the composition is usedin step (a).

In certain embodiments, the granulation fluid used in step (b) maycomprise water, a suitable solvent (e.g., ethanol, isopropanol, etc.),or combinations thereof. In one embodiment, the granulation fluidcomprises water. In one embodiment, the active ingredient may becombined with a portion of the filler, while a portion of the releasecontrol polymer (e.g., HPMC) is dissolved in a liquid, such as water, toform the granulation fluid. In one embodiment, the granulation fluid issprayed on the dry granulation mixture.

The dried granulation material may be milled using, for example, acomill fit with any suitable screen size. In one embodiment, the screensize is from about 600 to about 900 microns, or from about 610 to about813 microns. In one embodiment, the granulated material is milled usinga comill fitted with a 610 μm screen. In one embodiment, the granulatedmaterial is milled using a comill fitted with a 813 μm screen.

In step (e), the milled granulation material is combined with anyremaining composition components, such as any remaining filler (e.g.,microcrystalline cellulose, such as Avicel® PH102), any remainingrelease control polymer, glidants, lubricants, pH modifiers,surfactants, and the like. In one embodiment, the filler and/or releasecontrol polymer included in the granulated material may be the same ordifferent than the filler and/or release control polymer added in step(e). For instance, in one embodiment, the filler included in thegranulated material (e.g., Avicel®PH101) may have a smaller particlesize distribution than the filler added in step (e) (e.g., Avicel®PH102).

In one embodiment, the composition may be sieved, and the sievedcomposition blended, for example, after step (e), and prior tocompressing the composition (step (f)). In one embodiment, theformulation is sieved prior to addition of any lubricant. In oneembodiment, the pH modifier (e.g., tartaric acid) is optionally milledprior to combining with the granulated material.

In one embodiment, the present disclosure is directed to a process forpreparing a pharmaceutical composition, the process comprising: (a)combining an active ingredient (e.g., Compound 1 or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1) and atleast a portion of one additional composition component to form a drygranulation mixture; (b) contacting the dry granulation mixture with agranulation fluid to form a wet granulation mixture; (c) drying the wetgranulation mixture to form a granulated material; (d) milling thegranulated material to form a milled granulated material; (e) combiningthe milled granulation material with the remaining compositioncomponents; and (f) compressing the composition to form thepharmaceutical composition. In one embodiment, the method furtheroptionally comprises coating the pharmaceutical composition. In oneembodiment, the disclosure is directed to a pharmaceutical compositionprepared by this wet granulation process. In one embodiment, thepharmaceutical composition is a tablet. In one embodiment, the pHmodifier (e.g., tartaric acid) is optionally milled prior tocompressing. In one embodiment, the solid state form is Freebase HydrateForm C.

In some embodiments, the compressed and/or milled tablet comprises acrystalline solid state form of Compound 1. In one embodiment, thecrystalline solid state form is a crystalline hydrate. In oneembodiment, the crystalline solid state form is Freebase Hydrate Form C.Advantageously, it has been discovered that crystalline Freebase HydrateForm C is stable under mechanical processing, and exhibits minimalissues upon milling. In other embodiments, the crystalline solid stateform is a crystalline anhydrate. In one embodiment, the crystallineanhydrate is Freebase Anhydrate Form D.

In some embodiments, the pharmaceutical composition is a compressedand/or milled tablet comprising Compound 1, wherein at least about 75%by weight of the Compound 1 present in the tablet is Freebase HydrateForm C. In one aspect, at least 80% by weight is the Freebase HydrateForm C. In another aspect, at least 85% by weight is the FreebaseHydrate Form C. In another aspect, at least 90% by weight is theFreebase Hydrate Form C. In another aspect, at least 95% by weight isthe Freebase Hydrate Form C. In another aspect, at least 96% by weightis the Freebase Hydrate Form C. In another aspect, at least 97% byweight is the Freebase Hydrate Form C. In another aspect, at least 98%by weight is the Freebase Hydrate Form C. In another aspect, at least99% by weight is the Freebase Hydrate Form C.

In some embodiments, the pharmaceutical composition is a compressedand/or milled tablet comprising Compound 1, wherein at least about 75%by weight of the Compound 1 present in the tablet is the AmorphousFreebase. In one aspect, at least 80% by weight is the AmorphousFreebase. In another aspect, at least 85% by weight is the AmorphousFreebase. In another aspect, at least 90% by weight is the AmorphousFreebase. In another aspect, at least 95% by weight is the AmorphousFreebase. In another aspect, at least 96% by weight is the AmorphousFreebase. In another aspect, at least 97% by weight is the AmorphousFreebase. In another aspect, at least 98% by weight is the AmorphousFreebase. In another aspect, at least 99% by weight is the AmorphousFreebase.

In some embodiments, the pharmaceutical composition is a compressedand/or milled tablet comprising Compound 1, wherein at least about 75%by weight of the Compound 1 present in the tablet is the FreebaseHydrate Form B. In one aspect, at least 80% by weight is the FreebaseHydrate Form B. In another aspect, at least 85% by weight is theFreebase Hydrate Form B. In another aspect, at least 90% by weight isthe Freebase Hydrate Form B. In another aspect, at least 95% by weightis the Freebase Hydrate Form B. In another aspect, at least 96% byweight is the Freebase Hydrate Form B. In another aspect, at least 97%by weight is the Freebase Hydrate Form B. In another aspect, at least98% by weight is the Freebase Hydrate Form B. In another aspect, atleast 99% by weight is the Freebase Hydrate Form B.

In some embodiments, the pharmaceutical composition is a compressedand/or milled tablet comprising Compound 1, wherein at least about 75%by weight of the Compound 1 present in the tablet is Freebase AnhydrateForm D. In one aspect, at least 80% by weight is the Freebase AnhydrateForm D. In another aspect, at least 85% by weight is the FreebaseAnhydrate Form D. In another aspect, at least 90% by weight is theFreebase Anhydrate Form D. In another aspect, at least 95% by weight isthe Freebase Anhydrate Form D. In another aspect, at least 96% by weightis the Freebase Anhydrate Form D. In another aspect, at least 97% byweight is the Freebase Anhydrate Form D. In another aspect, at least 98%by weight is the Freebase Anhydrate Form D. In another aspect, at least99% by weight is the Freebase Anhydrate Form D.

In some embodiments, the pharmaceutical composition is a compressedand/or milled tablet comprising Compound 1, wherein at least about 75%by weight of the Compound 1 present in the tablet is the crystallinetartrate. In one aspect, at least 80% by weight is the crystallinetartrate. In another aspect, at least 85% by weight is the crystallinetartrate. In another aspect, at least 90% by weight is the crystallinetartrate. In another aspect, at least 95% by weight is the crystallinetartrate. In another aspect, at least 96% by weight is the crystallinetartrate. In another aspect, at least 97% by weight is the crystallinetartrate. In another aspect, at least 98% by weight is the crystallinetartrate. In another aspect, at least 99% by weight is the crystallinetartrate.

In one embodiment, the pharmaceutical composition is a tablet comprisinga solid state form of Compound 1 and a pharmaceutically acceptablecarrier, wherein the tablet is prepared by compressing the solid stateform of Compound 1 and the pharmaceutically acceptable carrier. In oneembodiment, the solid state form of Compound 1 is milled prior tocompressing. In one embodiment, the solid state form is Freebase HydrateForm C.

In some embodiments, the tablet further comprises a film coat. A filmcoat on the tablet further may contribute to the ease with which it canbe swallowed. A film coat can also improve taste and provides an elegantappearance. In certain embodiments, the film-coat includes a polymericfilm-forming material such as hydroxypropyl methylcellulose,hydroxypropylcellulose, and acrylate or methacrylate copolymers. Besidesa film-forming polymer, the film-coat may further comprise aplasticizer, e.g. polyethylene glycol, a surfactant, e.g. polysorbates,and optionally a pigment, e.g. titanium dioxide or iron oxides. Thefilm-coating may also comprise talc as anti-adhesive. In one embodiment,the film coat accounts for less than 5% by weight of a pharmaceuticalcomposition of the present invention.

In another embodiment, the pharmaceutical composition is a capsuledosage form.

In another embodiment, the pharmaceutical composition comprises acrystalline hydrate of Compound 1, wherein at least about 75% by weightof Compound 1 present in the composition is the crystalline hydrate ofCompound 1. In one aspect, at least 80% by weight is the crystallinehydrate. In another aspect, at least 85% by weight is the crystallinehydrate. In another aspect, at least 90% by weight is the crystallinehydrate. In another aspect, at least 95% by weight is the crystallinehydrate. In another aspect, at least 96% by weight is the crystallinehydrate. In another aspect, at least 97% by weight is the crystallinehydrate. In another aspect, at least 98% by weight is the crystallinehydrate. In another aspect, at least 99% by weight is the crystallinehydrate. In another aspect, the crystalline hydrate is the FreebaseHydrate Form C.

In another embodiment, the pharmaceutical composition comprises acrystalline tartrate of Compound 1, wherein at least about 75% by weightof Compound 1 present in the composition is the crystalline tartrate ofCompound 1. In one aspect, at least 80% by weight is the crystallinetartrate. In another aspect, at least 85% by weight is the crystallinetartrate. In another aspect, at least 90% by weight is the crystallinetartrate. In another aspect, at least 95% by weight is the crystallinetartrate. In another aspect, at least 96% by weight is the crystallinetartrate. In another aspect, at least 97% by weight is the crystallinetartrate. In another aspect, at least 98% by weight is the crystallinetartrate. In another aspect, at least 99% by weight is the crystallinetartrate. In another aspect, the crystalline hydrate is the TartrateHydrate. In one embodiment, the pharmaceutical composition comprises acrystalline tartrate of Compound 1, from about 10 w/w % to about 35 w/w% of an organic acid selected from the group consisting of tartaricacid, fumaric acid, citric acid, succinic acid, malic acid, andcombinations thereof, and a pharmaceutically acceptable carrier. In oneembodiment, the crystalline hydrate is the Tartrate Hydrate.

In another embodiment, the pharmaceutical composition comprises theAmorphous Freebase, wherein at least about 75% by weight of Compound 1present in the composition is the Amorphous Freebase. In one aspect, atleast 80% by weight is the Amorphous Freebase. In another aspect, atleast 85% by weight is the Amorphous Freebase. In another aspect, atleast 90% by weight is the Amorphous Freebase. In another aspect, atleast 95% by weight is the Amorphous Freebase. In another aspect, atleast 96% by weight is the Amorphous Freebase. In another aspect, atleast 97% by weight is the Amorphous Freebase. In another aspect, atleast 98% by weight is the Amorphous Freebase. In another aspect, atleast 99% by weight is the Amorphous Freebase.

In another embodiment, the pharmaceutical composition comprises acrystalline anhydrate of Compound 1, wherein at least about 75% byweight of Compound 1 present in the composition is the crystallineanhydrate of Compound 1. In one aspect, at least 80% by weight is thecrystalline anhydrate. In another aspect, at least 85% by weight is thecrystalline anhydrate. In another aspect, at least 90% by weight is thecrystalline anhydrate. In another aspect, at least 95% by weight is thecrystalline anhydrate. In another aspect, at least 96% by weight is thecrystalline anhydrate. In another aspect, at least 97% by weight is thecrystalline anhydrate. In another aspect, at least 98% by weight is thecrystalline anhydrate. In another aspect, at least 99% by weight is thecrystalline anhydrate. In another aspect, the crystalline anhydrate isthe Freebase Anhydrate Form D.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Compound 1 freebaseor a pharmaceutically acceptable salt thereof or a solid state form ofCompound 1, and a pharmaceutically acceptable carrier, wherein the solidstate form of Compound 1 is selected from the group consisting ofAmorphous Freebase, Freebase Hydrate Form B, Freebase Hydrate Form C,and Freebase Anhydrate Form D. In some such embodiments, thepharmaceutical composition is a once daily extended release dosage form(e.g., tablet or capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Compound 1 freebaseor a pharmaceutically acceptable salt thereof or a solid state form ofCompound 1, a pharmaceutically acceptable carrier, and a pH modifier,wherein the solid state form of Compound 1 is selected from the groupconsisting of Amorphous Freebase, Freebase Hydrate Form B, FreebaseHydrate Form C, and Freebase Anhydrate Form D. In one embodiment, thepharmaceutical composition comprises from about 10 wt % to about 30 wt.% of the pH modifier. In one embodiment, the pH modifier is tartaricacid. In some such embodiments, the pharmaceutical composition is a oncedaily extended release dosage form (e.g., tablet or capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of a solid state formof Compound 1, a pharmaceutically acceptable carrier, and from about 10w/w % to about 35 w/w % of tartaric acid, wherein the solid state formof Compound 1 is selected from the group consisting of AmorphousFreebase, Freebase Hydrate Form B, Freebase Hydrate Form C, and FreebaseAnhydrate Form D. In some such embodiments, the pharmaceuticalcomposition is a once daily extended release dosage form (e.g., tabletor capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Freebase HydrateForm B, a pharmaceutically acceptable carrier, and from about 10 w/w %to about 35 w/w % of tartaric acid. In some such embodiments, thepharmaceutical composition is a once daily extended release dosage form(e.g., tablet or capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Amorphous Freebase,a pharmaceutically acceptable carrier, and from about 10 w/w % to about35 w/w % of tartaric acid. In some such embodiments, the pharmaceuticalcomposition is a once daily extended release dosage form (e.g., tabletor capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Freebase AnhydrateForm D, a pharmaceutically acceptable carrier, and from about 10 w/w %to about 35 w/w % of tartaric acid. In some such embodiments, thepharmaceutical composition is a once daily extended release dosage form(e.g., tablet or capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and from about 10 w/w %to about 35 w/w % of tartaric acid. In some such embodiments, thepharmaceutical composition is a once daily extended release dosage form(e.g., tablet or capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and about 10 w/w % oftartaric acid. In some such embodiments, the pharmaceutical compositionis a once daily extended release dosage form (e.g., tablet or capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and about 20 w/w % oftartaric acid. In some such embodiments, the pharmaceutical compositionis a once daily extended release dosage form (e.g., tablet or capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and about 30 w/w % oftartaric acid. In some such embodiments, the pharmaceutical compositionis a once daily extended release dosage form (e.g., tablet or capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Compound 1 freebaseor a pharmaceutically acceptable salt thereof or a solid state form ofCompound 1, and a pharmaceutically acceptable carrier, wherein the solidstate form of Compound 1 is selected from the group consisting ofAmorphous Freebase, Freebase Hydrate Form B, Freebase Hydrate Form C,and Freebase Anhydrate Form D. In some such embodiments, thepharmaceutical composition is a once daily extended release dosage form(e.g., tablet or capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Compound 1 freebaseor a pharmaceutically acceptable salt thereof or a solid state form ofCompound 1, a pharmaceutically acceptable carrier, and a pH modifier,wherein the solid state form of Compound 1 is selected from the groupconsisting of Amorphous Freebase, Freebase Hydrate Form B, FreebaseHydrate Form C, and Freebase Anhydrate Form D. In one embodiment, thepharmaceutical composition comprises from about 10 wt % to about 30 wt.% of the pH modifier. In one embodiment, the pH modifier is tartaricacid. In some such embodiments, the pharmaceutical composition is a oncedaily extended release dosage form (e.g., tablet or capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of a solid state formof Compound 1, a pharmaceutically acceptable carrier, and from about 10w/w % to about 35 w/w % of tartaric acid, wherein the solid state formof Compound 1 is selected from the group consisting of AmorphousFreebase, Freebase Hydrate Form B, Freebase Hydrate Form C, and FreebaseAnhydrate Form D. In some such embodiments, the pharmaceuticalcomposition is a once daily extended release dosage form (e.g., tabletor capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Freebase HydrateForm B, a pharmaceutically acceptable carrier, and from about 10 w/w %to about 35 w/w % of tartaric acid. In some such embodiments, thepharmaceutical composition is a once daily extended release dosage form(e.g., tablet or capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Amorphous Freebase,a pharmaceutically acceptable carrier, and from about 10 w/w % to about35 w/w % of tartaric acid. In some such embodiments, the pharmaceuticalcomposition is a once daily extended release dosage form (e.g., tabletor capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Freebase AnhydrateForm D, a pharmaceutically acceptable carrier, and from about 10 w/w %to about 35 w/w % of tartaric acid. In some such embodiments, thepharmaceutical composition is a once daily extended release dosage form(e.g., tablet or capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and from about 10 w/w %to about 35 w/w % of tartaric acid. In some such embodiments, thepharmaceutical composition is a once daily extended release dosage form(e.g., tablet or capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and about 10 w/w % oftartaric acid. In some such embodiments, the pharmaceutical compositionis a once daily extended release dosage form (e.g., tablet or capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and about 20 w/w % oftartaric acid. In some such embodiments, the pharmaceutical compositionis a once daily extended release dosage form (e.g., tablet or capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and about 30 w/w % oftartaric acid. In some such embodiments, the pharmaceutical compositionis a once daily extended release dosage form (e.g., tablet or capsule).

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1, and apharmaceutically acceptable carrier, wherein the pharmaceuticalcomposition is a once daily extended release dosage form (e.g., tabletor capsule) that sustains release of the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 for from about 4 hours to about 24 hours following entry ofthe dosage form into a use environment, and wherein the dosage form hasa release rate of not more than about 60% after passage of about 4 hoursfollowing entry of the dosage form into a use environment. In some suchembodiments, the dosage form has a release rate of not more than about60% after passage of about 4 hours following entry of the dosage forminto a use environment, from about 50% to about 80% after passage ofabout 8 hours following entry of the dosage form into a use environment,from about 55% to about 90% after passage of about 10 hours followingentry of the dosage form into a use environment, and from about 70% to100% after passage of about 20 hours following entry of the dosage forminto a use environment. In some embodiments, the solid state form ofCompound 1 is selected from the group consisting of Amorphous Freebase,Freebase Hydrate Form B, Freebase Hydrate Form C, and Freebase AnhydrateForm D,

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of a solid state formof Compound 1, a pharmaceutically acceptable carrier, and from about 10w/w % to about 35 w/w % of tartaric acid, wherein the solid state formof Compound 1 is selected from the group consisting of AmorphousFreebase, Freebase Hydrate Form B, Freebase Hydrate Form C, and FreebaseAnhydrate Form D, and the pharmaceutical composition is a once dailyextended release dosage form (e.g., tablet or capsule) that sustainsrelease of the Compound 1 freebase or the solid state form of Compound 1for from about 4 hours to about 24 hours following entry of the dosageform into a use environment, and wherein the dosage form has a releaserate of not more than about 60% after passage of about 4 hours followingentry of the dosage form into a use environment. In some suchembodiments, the dosage form has a release rate of not more than about60% after passage of about 4 hours following entry of the dosage forminto a use environment, from about 50% to about 80% after passage ofabout 8 hours following entry of the dosage form into a use environment,from about 55% to about 90% after passage of about 10 hours followingentry of the dosage form into a use environment, and from about 70% to100% after passage of about 20 hours following entry of the dosage forminto a use environment.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and from about 10 w/w %to about 35 w/w % of tartaric acid, wherein the pharmaceuticalcomposition is a once daily extended release dosage form (e.g., tabletor capsule) that sustains release of the Compound 1 freebase or thesolid state form of Compound 1 for from about 4 hours to about 24 hoursfollowing entry of the dosage form into a use environment, and whereinthe dosage form has a release rate of not more than about 60% afterpassage of about 4 hours following entry of the dosage form into a useenvironment, from about 50% to about 80% after passage of about 8 hoursfollowing entry of the dosage form into a use environment, from about55% to about 90% after passage of about 10 hours following entry of thedosage form into a use environment, and from about 70% to 100% afterpassage of about 20 hours following entry of the dosage form into a useenvironment.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of a solid state formof Compound 1, a pharmaceutically acceptable carrier, and from about 10w/w % to about 35 w/w % of tartaric acid, wherein the solid state formof Compound 1 is selected from the group consisting of AmorphousFreebase, Freebase Hydrate Form B, Freebase Hydrate Form C, and FreebaseAnhydrate Form D, and the pharmaceutical composition is a once dailyextended release dosage form (e.g., tablet or capsule) that sustainsrelease of the Compound 1 freebase or the solid state form of Compound 1for from about 4 hours to about 24 hours following entry of the dosageform into a use environment, and wherein the dosage form has a releaserate of not more than about 60% after passage of about 4 hours followingentry of the dosage form into a use environment. In some suchembodiments, the dosage form has a release rate of not more than about60% after passage of about 4 hours following entry of the dosage forminto a use environment, from about 50% to about 80% after passage ofabout 8 hours following entry of the dosage form into a use environment,from about 55% to about 90% after passage of about 10 hours followingentry of the dosage form into a use environment, and from about 70% to100% after passage of about 20 hours following entry of the dosage forminto a use environment.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and from about 10 w/w %to about 35 w/w % of tartaric acid, wherein the pharmaceuticalcomposition is a once daily extended release dosage form (e.g., tabletor capsule) that sustains release of the Compound 1 freebase or thesolid state form of Compound 1 for from about 4 hours to about 24 hoursfollowing entry of the dosage form into a use environment, and whereinthe dosage form has a release rate of not more than about 60% afterpassage of about 4 hours following entry of the dosage form into a useenvironment, from about 50% to about 80% after passage of about 8 hoursfollowing entry of the dosage form into a use environment, from about55% to about 90% after passage of about 10 hours following entry of thedosage form into a use environment, and from about 70% to 100% afterpassage of about 20 hours following entry of the dosage form into a useenvironment.

In some of the foregoing embodiments, the dosage form releases theactive ingredient (i.e., Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1), at arelease rate of not more than about 25%, or from about 10% to about 25%,or from about 15% to about 20%, or about 20% after passage of about 1hour following entry into the use environment. In one embodiment, thedosage form releases the active ingredient at a release rate of not morethan about 40%, or from about 20% to about 40%, or from about 25% toabout 35% after passage of about 2 hours following entry into the useenvironment. In one embodiment, the dosage form releases the activeingredient at a release rate of not more than about 60%, or from about30% to about 60%, or from about 40% to about 60%, or from about 45% toabout 55% after passage of about 4 hours following entry into the useenvironment. In one embodiment, the dosage form releases the activeingredient at a release rate of not more than about 70% or from about40% to about 70%, or from about 55% to about 70% after passage of about6 hours following entry into the use environment. In one embodiment, thedosage form releases the active ingredient at a release rate of not morethan about 80% or from about 55% to about 80%, or from about 60% toabout 80% after passage of about 6 hours following entry into the useenvironment. In one embodiment, the dosage form releases the activeingredient at a release rate of not more than about 80%, or not lessthan about 50%, or not less than about 60%, or not less than about 70%,or not less than about 75%, or from about 50% to about 80%, or fromabout 60% to about 80%, or from about 65% to about 80% after passage ofabout 8 hours following entry into the use environment. In oneembodiment, the dosage form releases the active ingredient at a releaserate of not less than about 55%, or not less than about 60% or not lessthan about 70%, or not less than about 80%, or not less than about 85%,or from about 55% to about 90%, or from about 70% to about 90% afterpassage of about 10 hours following entry into the use environment. Inone embodiment, the dosage form releases the active ingredient at arelease rate of not less than about 65%, or not less than about 70%, ornot less than about 80%, or not less than about 90%, or from about 65%to about 99%, or from about 80% to about 99%, or from about 90% to about99% after passage of about 16 hours following entry into the useenvironment. In one embodiment, the dosage form releases the activeingredient at a release rate of not less than about 70%, or not lessthan about 80%, or not less than about 90%, or from about 70% to 100%,or from about 80% to 100% after passage of about 20 hours followingentry into the use environment. In one aspect, the dosage form has arelease rate of not more than about 60% after passage of about 4 hoursfollowing entry of the dosage form into a use environment, from about50% to about 80% after passage of about 8 hours following entry of thedosage form into a use environment, from about 55% to about 90% afterpassage of about 10 hours following entry of the dosage form into a useenvironment, and from about 70% to 100% after passage of about 20 hoursfollowing entry of the dosage form into a use environment.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1, and apharmaceutically acceptable carrier, wherein the solid state form ofCompound 1 is selected from the group consisting of Amorphous Freebase,Freebase Hydrate Form B, Freebase Hydrate Form C, and Freebase AnhydrateForm D, wherein the pharmaceutical composition is a once daily extendedrelease dosage form (e.g., tablet or capsule) that, when added to a testmedium comprising 900 mL of 50 mM pH 6.8 sodium phosphate buffer at 37°C.±0.5° C. in a standard USP rotating paddle apparatus when the paddlesare rotated at 75 rpm±4%, dissolves not more than about 60% of Compound1 freebase or the solid state form of Compound 1 after passage of about4 hours, from about 50% to about 80% of Compound 1 freebase or the solidstate form of Compound 1 after passage of about 8 hours, from about 55%to about 90% of Compound 1 freebase or the solid state form of Compound1 after passage of about 10 hours, and from about 70% to 100% ofCompound 1 freebase or the solid state form of Compound 1 after passageof about 20 hours.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of a solid state formof Compound 1, a pharmaceutically acceptable carrier, and from about 10wt % to about 30 wt % of tartaric acid, wherein the solid state form ofCompound 1 is selected from the group consisting of Amorphous Freebase,Freebase Hydrate Form B, Freebase Hydrate Form C, and Freebase AnhydrateForm D, wherein the pharmaceutical composition is a once daily extendedrelease dosage form (e.g., tablet or capsule) that, when added to a testmedium comprising 900 mL of 50 mM pH 6.8 sodium phosphate buffer at 37°C.±0.5° C. in a standard USP rotating paddle apparatus when the paddlesare rotated at 75 rpm±4%, dissolves not more than about 60% of Compound1 freebase or the solid state form of Compound 1 after passage of about4 hours, from about 50% to about 80% of Compound 1 freebase or the solidstate form of Compound 1 after passage of about 8 hours, from about 55%to about 90% of Compound 1 freebase or the solid state form of Compound1 after passage of about 10 hours, and from about 70% to 100% ofCompound 1 freebase or the solid state form of Compound 1 after passageof about 20 hours.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and from about 10 wt % toabout 30 wt % of tartaric acid, wherein the pharmaceutical compositionis a once daily extended release dosage form (e.g., tablet or capsule)that, when added to a test medium comprising 900 mL of 50 mM pH 6.8sodium phosphate buffer at 37° C.±0.5° C. in a standard USP rotatingpaddle apparatus when the paddles are rotated at 75 rpm±4%, dissolvesnot more than about 60% of Compound 1 freebase or the solid state formof Compound 1 after passage of about 4 hours, from about 50% to about80% of Compound 1 freebase or the solid state form of Compound 1 afterpassage of about 8 hours, from about 55% to about 90% of Compound 1freebase or the solid state form of Compound 1 after passage of about 10hours, and from about 70% to 100% of Compound 1 freebase or the solidstate form of Compound 1 after passage of about 20 hours.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of a solid state formof Compound 1, a pharmaceutically acceptable carrier, and from about 10wt % to about 30 wt % of tartaric acid, wherein the solid state form ofCompound 1 is selected from the group consisting of Amorphous Freebase,Freebase Hydrate Form B, Freebase Hydrate Form C, and Freebase AnhydrateForm D, wherein the pharmaceutical composition is a once daily extendedrelease dosage form (e.g., tablet or capsule) that, when added to a testmedium comprising 900 mL of 50 mM pH 6.8 sodium phosphate buffer at 37°C.±0.5° C. in a standard USP rotating paddle apparatus when the paddlesare rotated at 75 rpm±4%, dissolves not more than about 60% of Compound1 freebase or the solid state form of Compound 1 after passage of about4 hours, from about 50% to about 80% of Compound 1 freebase or the solidstate form of Compound 1 after passage of about 8 hours, from about 55%to about 90% of Compound 1 freebase or the solid state form of Compound1 after passage of about 10 hours, and from about 70% to 100% ofCompound 1 freebase or the solid state form of Compound 1 after passageof about 20 hours.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and from about 10 wt % toabout 30 wt % of tartaric acid, wherein the pharmaceutical compositionis a once daily extended release dosage form (e.g., tablet or capsule)that, when added to a test medium comprising 900 mL of 50 mM pH 6.8sodium phosphate buffer at 37° C.±0.5° C. in a standard USP rotatingpaddle apparatus when the paddles are rotated at 75 rpm±4%, dissolvesnot more than about 60% of Compound 1 freebase or the solid state formof Compound 1 after passage of about 4 hours, from about 50% to about80% of Compound 1 freebase or the solid state form of Compound 1 afterpassage of about 8 hours, from about 55% to about 90% of Compound 1freebase or the solid state form of Compound 1 after passage of about 10hours, and from about 70% to 100% of Compound 1 freebase or the solidstate form of Compound 1 after passage of about 20 hours.

VII. PHARMACOKINETIC PARAMETERS

15 mg Dosage Formulations

In certain embodiments, the methods of the present disclosure compriseadministering to an adult subject (e.g., a human subject) Compound 1(freebase), or a pharmaceutically acceptable salt thereof, or acrystalline hydrate of Compound 1 in an amount sufficient to deliver tothe subject 15 mg of Compound 1 freebase equivalent. In one embodiment,the freebase or the hydrate is in a once daily extended releaseformulation.

Unless otherwise indicated, the following pharmacokinetic parameters areachieved after administration of a single 15 mg dose the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate (e.g., Freebase Hydrate Form C) to the adultsubject, or after administration of a sufficient number of once-daily 15mg doses to achieve a steady-state. By a single 15 mg dose, it is meanta single dosage unit containing an amount of freebase orpharmaceutically acceptable salt or crystalline hydrate sufficient todeliver to the subject 15 mg of Compound 1 freebase equivalent. In oneembodiment, the single dosage unit is a once daily extended releaseformulation.

In certain embodiments, the administration of the Compound 1 (freebase)or a pharmaceutically acceptable salt thereof or the crystalline hydrateto the adult subject achieves a mean C_(max) for Compound 1 of fromabout 25 to about 70 ng/mL, after a single 15 mg dose. In someembodiments, when administered to the adult subject, the Compound 1(freebase) or the crystalline hydrate achieve a mean C_(max) forCompound 1 of from about 25.0 to about 60.0 ng/mL, or from about 25.0 toabout 40.0 ng/mL, from about 25.0 to about 30.0 ng/mL, or about 25.0 toabout 28.0 ng/mL, or about 25.0 to about 27.0 ng/mL, or about 27.0 toabout 40.0 ng/mL, or about 27.0 to about 35.0 ng/mL, or about 27.0 toabout 30.0 ng/mL, or about 27.0 to about 29.0 ng/mL, or about 28.0 toabout 30.0 ng/mL, or about 29.0 to about 31.0 ng/mL, or about 30.0 toabout 32.0 ng/mL, after a single 15 mg dose. In some embodiments, whenadministered to the adult subject, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a mean C_(max) for Compound 1 of from about 26.0 to about 26.4ng/mL, or from about 26.2 to about 26.6 ng/mL, or from about 26.4 toabout 26.8 ng/mL, or from about 26.6 to about 27.0 ng/mL, or from about26.8 to about 27.2 ng/mL, or from about 27.0 to about 27.4 ng/mL, orfrom about 27.2 to about 27.6 ng/mL, or from about 27.4 to about 27.8ng/mL, or from about 27.6 to about 28.0 ng/mL, or from about 27.8 toabout 28.2 ng/mL, or from about 28.0 to about 28.4 ng/mL, or from about28.2 to about 28.6 ng/mL, or from about 28.4 to about 28.8 ng/mL, orfrom about 28.6 to about 29.0 ng/mL, or from about 28.8 to about 29.2ng/mL, or from about 29.0 to about 29.4 ng/mL, or from about 29.2 toabout 29.6 ng/mL, or from about 29.4 to about 29.8 ng/mL, or from about29.6 to about 30.0 ng/mL, or from about 29.8 to about 30.2 ng/mL, orfrom about 30.0 to about 30.4 ng/mL, or from about 30.2 to about 30.6ng/mL, or from about 30.4 to about 30.8 ng/mL, or from about 30.6 toabout 31.0 ng/mL, or from about 30.8 to about 31.2 ng/mL, or from about31.0 to about 31.4 ng/mL, or from about 31.2 to about 31.6 ng/mL, orfrom about 31.4 to about 31.8 ng/mL, or from about 31.6 to about 32.0ng/mL, after a single 15 mg dose.

In some embodiments, when administered to the adult subject underfasting conditions, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate achieve a meanC_(max) for Compound 1 of about 26 ng/mL or about 32 ng/mL, after asingle 15 mg dose. In other embodiments, when administered to the adultsubject under non-fasting conditions, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a mean C_(max) for Compound 1 of about 37 ng/mL or about 40ng/mL after a single 15 mg dose.

In certain embodiments, when the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrate isadministered to the adult subject, the difference in the C_(max) forCompound 1 after a single 15 mg dose in the fed versus the fasted stateis selected from about 30% or less, about 20% or less, and about 10% orless. As used herein, a subject in a “fed” state (also referred toherein as “non-fasting” state or “non-fasting conditions”) is one whohas consumed a standard or high-fat meal within about 30 minutes priorto administration of the drug. As used herein, a subject in a “fasted”state (also referred to herein as “fasting conditions”) refers to asubject who has fasted for at least 10 hours prior to initialadministration the drug, or, if the subject is being administered thedrug over multiple days, refers to a subject who has fasted for at leasttwo hours prior to each subsequent administration of the drug.

When administered to the adult subject, in certain embodiments, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a T_(max) for Compound 1 from about 1.0to about 6.0 hours after a single 15 mg dose. In some embodiments, whenadministered to the adult subject, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a T_(max) for Compound 1 of from about 1.0 to about 5.0 hours,or from about 1.0 to about 4.0 hours, or from about 1.0 to about 3.0hours, or from about 1.0 to about 2.0 hours, or from about 2.0 to about6.0 hours, or from about 3.0 to about 6.0 hours, or from about 4.0 toabout 6.0 hours, or from about 5.0 to about 6.0 hours, or from about 2.0to about 5.0 hours, or from about 2.0 to about 4.0 hours, or from about2.0 to about 3.0 hours, or from about 3.0 to about 4.0 hours, or fromabout 3.0 to about 5.0 hours, or from about 4.0 to about 5.0 hours,after a single 15 mg dose. In some embodiments, when administered to theadult subject, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate achieve a T_(max) forCompound 1 of from about 2.6 to about 3.0 hours, or from about 2.8 toabout 3.2 hours, or from about 3.0 to about 3.4 hours, or from about 3.2to about 3.6 hours, or from about 3.4 to about 3.8 hours, or from about3.6 to about 4.0 hours, or from about 3.8 to about 4.2 hours, or fromabout 4.0 to about 4.4 hours, after a single 15 mg dose.

In other embodiments, when administered to the adult subject underfasting conditions, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate achieve a T_(max) forCompound 1 of from about 1.0 to about 4.0 hours after a single 15 mgdose, or achieve a T_(max) for Compound 1 from about 1.5 to about 6.0hours after a single 15 mg dose, or achieve a median T_(max) forCompound 1 of about 3.0 hours after a single 15 mg dose. In otherembodiments, when administered to the adult subject under non-fastingconditions, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a T_(max) for Compound 1from about 3.0 to about 6.0 hours after a single 15 mg dose, or achievea median T_(max) for Compound 1 of about 4.0 hours after a single 15 mgdose.

When administered to the adult subject, in certain embodiments, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a harmonic mean t_(1/2) for Compound 1of from about 10.0 to about 14.0 hours after a single 15 mg dose. Inother embodiments, when administered to an adult subject, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate achieve a harmonic mean t_(1/2) for Compound 1 offrom about 10.0 to about 13.0 hours, or from about 10.0 to about 12.0hours, or from about 10.0 to about 11.0 hours, or from about 11.0 toabout 14.0 hours, or from about 11.0 to about 13.0 hours, or from about11.0 to about 12.0 hours, or from about 12.0 to about 14.0 hours, orfrom about 12.0 to about 13.0 hours, or from about 13.0 to about 14.0hours, after a single 15 mg dose. In other embodiments, whenadministered to an adult subject, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a harmonic mean t_(1/2) for Compound 1 of from about 12.0 toabout 12.4 hours, or from about 12.2 to about 12.6 hours, or from about12.4 to about 12.8 hours, or from about 12.6 to about 13.0 hours, orfrom about 12.8 to about 13.2 hours, or from about 13.0 to about 13.4hours, or from about 13.4 to about 13.8 hours, or from about 13.6 toabout 14.0 hours, after a single 15 mg dose. In other embodiments, whenadministered to the adult subject, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a harmonic mean t_(1/2) for Compound 1 of about 12.5 hours aftera single 15 mg dose.

When administered to the adult subject, in certain embodiments, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a mean AUC_(inf) for Compound 1 of fromabout 220 to about 450 ng·hours/mL after a single 15 mg dose. Whenadministered to the adult subject, in certain embodiments, the Compound1 (freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate achieve a mean AUC_(inf) for Compound 1 of fromabout 220 to about 320 ng·hours/mL, or from about 220 to about 260ng·hours/mL, or from about 220 to about 250 ng·hours/mL, or from about220 to about 245 ng·hours/mL, or from about 230 to about 260ng·hours/mL, or from about 230 to about 250 ng·hours/mL, or from about230 to about 245 ng·hours/mL, or from about 240 to about 260ng·hours/mL, or from about 240 to about 250 ng·hours/mL, or from about242 to about 250 ng·hours/mL, or from about 240 to about 245 ng·hours/mLafter a single 15 mg dose. When administered to the adult subject, incertain embodiments, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate achieve a meanAUC_(inf) for Compound 1 of from about 238 to about 240 ng·hours/mL, orfrom about 239 to about 241 ng·hours/mL, or from about 240 to about 242ng·hours/mL, or from about 242 to about 244 ng·hours/mL, or from about243 to about 245 ng·hours/mL, or from about 244 to about 246ng·hours/mL, or from about 245 to about 247 ng·hours/mL, or from about246 to about 248 ng·hours/mL, or from about 247 to about 249 ng·hours/mLafter a single 15 mg dose.

When administered to the adult subject under fasting conditions, incertain embodiments, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate achieve a meanAUC_(inf) for Compound 1 of from about 240 to about 245 ng·hours/mL, orabout 242 ng·hours/mL after a single 15 mg dose.

When administered to the adult subject under fasting conditions, incertain embodiments, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate achieve a meanAUC_(t) for Compound 1 of about 227 ng·hours/mL after a single 15 mgdose, or achieve a mean AUC₂₄ for Compound 1 of about 249 ng·hours/mLafter a single 15 mg dose. When administered to the adult subject undernon-fasting conditions, in certain embodiments, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate achieve a mean AUC₂₄ for Compound 1 of about 305ng·hours/mL or about 318 ng·hours/mL after a single 15 mg dose.

In certain embodiments, when the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrate isadministered to the subject, the difference in the AUC_(inf) forCompound 1 after a 15 mg dose in the fed versus the fasted state isselected from about 30% or less, about 20% or less, and about 10% orless.

When administered to the adult subject, in certain embodiments, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a mean C₂₄ for Compound 1 of from about1.4 to about 2.5 ng/mL after a single 15 mg dose. When administered tothe adult subject under fasting conditions, in certain embodiments, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a mean C₂₄ for Compound 1 of about 1.5ng/mL or about 1.9 ng/mL after a single 15 mg dose. When administered tothe adult subject under non-fasting conditions, in certain embodiments,the Compound 1 (freebase) or a pharmaceutically acceptable salt thereofor the crystalline hydrate achieve a mean C₂₄ for Compound 1 of about2.4 ng/mL.

When administered QD (once-daily) to the adult subject, in certainembodiments the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a mean C_(max,ss), orCompound 1 of from about 27 to about 55 ng/mL. When administered QD(once-daily) to the adult subject, in certain embodiments the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate achieve a mean C_(max,ss) for Compound 1 of fromabout 27 to about 38 ng/mL, or from about 27 to about 36 ng/mL, or fromabout 27 to about 34 ng/mL, or from about 27 to about 32 ng/mL, or fromabout 27 to about 30 ng/mL, or from about 29 to about 38 ng/mL, or fromabout 29 to about 36 ng/mL, or from about 29 to about 34 ng/mL, or fromabout 29 to about 32 ng/mL, or from about 30 to about 36 ng/mL, or fromabout 30 to about 34 ng/mL. When administered QD (once-daily) to theadult subject, in certain embodiments the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a mean C_(max,ss) for Compound 1 of from about 31.0 to about31.4 ng/mL, or from about 31.2 to about 31.6 ng/mL, or from about 31.4to about 31.8 ng/mL, or from about 31.6 to about 32.0 ng/mL, or fromabout 31.8 to about 32.2 ng/mL, or from about 32.0 to about 32.4 ng/mL,or from about 32.2 to about 32.6 ng/mL, or from about 32.4 to about 32.8ng/mL, or from about 32.6 to about 33.0 ng/mL, or from about 32.8 toabout 33.2 ng/mL, or from about 33.0 to about 33.4 ng/mL, or from about33.2 to about 33.6 ng/mL, or from about 33.4 to about 33.8 ng/mL, orfrom about 33.6 to about 34.0 ng/mL, or from about 33.8 to about 34.2ng/mL, or from about 34.0 to about 34.4 ng/mL, or from about 34.2 toabout 34.6 ng/mL, or from about 34.4 to about 34.8 ng/mL, or from about34.6 to about 35.0 ng/mL, or from about 34.8 to about 35.2 ng/mL, orfrom about 35.0 to about 35.4 ng/mL, or from about 35.2 to about 35.6ng/mL, or from about 35.4 to about 35.8 ng/mL, or from about 35.6 toabout 36.0 ng/mL, or from about 35.8 to about 36.2 ng/mL, or from about36.0 to about 36.4 ng/mL, or from about 36.2 to about 36.6 ng/mL, orfrom about 36.4 to about 36.8 ng/mL, or from about 36.6 to about 37.0ng/mL, or from about 36.8 to about 37.2 ng/mL, or from about 37.0 toabout 37.4 ng/mL, or from about 37.2 to about 37.6 ng/mL, or from about37.4 to about 37.8 ng/mL, or from about 37.6 to about 38.0 ng/mL.

When administered QD (once-daily) to the adult subject under fastingconditions, in certain embodiments, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a mean C_(max,ss) for Compound 1 of about 32 ng/mL. Whenadministered QD (once-daily) to the adult subject under non-fastingconditions, in certain embodiments, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a mean C_(max,ss) for Compound 1 of about 36 ng/mL or about 37ng/mL.

When administered QD (once-daily) to the adult subject, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a T_(max,ss) forCompound 1 of from about 1.5 to about 6.0 hours. When administered QD(once-daily) to the adult subject, in certain embodiments, the Compound1 (freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate achieve a T_(max,ss) for Compound 1 of from about1.5 to about 5.0 hours, or from about 1.5 to about 4.0 hours, or fromabout 1.5 to about 3.0 hours, or from about 1.5 to about 2.0 hours, orfrom about 2.0 to about 6.0 hours, or from about 3.0 to about 6.0 hours,or from about 4.0 to about 6.0 hours, or from about 2.0 to about 5.0hours, or from about 2.0 to about 4.0 hours, or from about 2.0 to about3.0 hours, or from about 3.0 to about 5.0 hours, or from about 3.0 toabout 4.0 hours, or from about 4.0 to about 5.0 hours. In someembodiments, when administered QD (once-daily) to the adult subject, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a T_(max,ss) for Compound 1 of fromabout 2.6 to about 3.0 hours, or from about 2.8 to about 3.2 hours, orfrom about 3.0 to about 3.4 hours, or from about 3.2 to about 3.6 hours,or from about 3.4 to about 3.8 hours, or from about 3.6 to about 4.0hours, or from about 3.8 to about 4.2 hours, or from about 4.0 to about4.4 hours.

When administered QD (once-daily) to the adult subject under fastingconditions, in certain embodiments, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a T_(max,ss) for Compound 1 of from about 1.5 to about 4.0hours, or achieve a median T_(max,ss) for Compound 1 of about 2.5 hours.When administered QD (once-daily) to the adult subject under non-fastingconditions, in certain embodiments, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a T_(max,ss) for Compound 1 of from about 2.0 to about 6.0hours, or achieve a median T_(max,ss) for Compound 1 of about 4.0 hours.

When administered QD (once-daily) to the adult subject, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a mean C_(trough) forCompound 1 of from about 2.5 to about 5.1 ng/mL. When administered QD(once-daily) to the adult subject under fasting conditions, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a mean C_(trough) forCompound 1 of about 2.8 ng/mL. When administered QD (once-daily) to theadult subject under non-fasting conditions, in certain embodiments, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a mean C_(trough) for Compound 1 of fromabout 2.5 to about 5.1 ng/mL, or from about 2.5 to about 3.6 ng/mL, orachieve a mean C_(trough) for Compound 1 of about 2.6 ng/mL or about 3.2ng/mL or about 3.6 ng/mL, or about 5.0 ng/mL.

When administered QD (once-daily) to the adult subject, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a mean AUC_(24,ss) forCompound 1 of from about 240 to about 325 ng·hours/mL. When administeredQD (once-daily) to the adult subject, in certain embodiments, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a mean AUC_(24,ss) for Compound 1 offrom about 240 to about 290 ng·hours/mL, or from about 240 to about 280ng·hours/mL, or from about 240 to about 260 ng·hours/mL, or from about250 to about 290 ng·hours/mL, or from about 250 to about 280ng·hours/mL, or from about 260 to about 280 ng·hours/mL, or from about270 to about 280 ng·hours/mL, or from about 275 to about 280ng·hours/mL, or from about 279 to about 280 ng·hours/mL. Whenadministered QD (once-daily) to the adult subject, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a mean AUC_(24,ss) forCompound 1 of from about 240 to about 244 ng·hours/mL, or from about 241to about 245 ng·hours/mL, or from about 242 to about 246 ng·hours/mL, orfrom about 244 to about 248 ng·hours/mL, or from about 246 to about 250ng·hours/mL, or from about 248 to about 252 ng·hours/mL, or from about250 to about 254 ng·hours/mL, or from about 252 to about 256ng·hours/mL, or from about 254 to about 258 ng·hours/mL, or from about256 to about 260 ng·hours/mL, or from about 258 to about 262ng·hours/mL, or from about 260 to about 264 ng·hours/mL, or from about262 to about 266 ng·hours/mL, or from about 264 to about 268ng·hours/mL, or from about 266 to about 270 ng·hours/mL, or from about268 to about 272 ng·hours/mL, or from about 270 to about 274ng·hours/mL, or from about 272 to about 276 ng·hours/mL, or from about274 to about 278 ng·hours/mL, or from about 276 to about 280ng·hours/mL.

When administered QD (once-daily) to the adult subject under fastingconditions, in certain embodiments, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a mean AUC_(24,ss) for Compound 1 of about 241 ng·hours/mL orabout 279 ng·hours/mL. When administered QD (once-daily) to the adultsubject under non-fasting conditions, in certain embodiments, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a mean AUC_(24,ss) for Compound 1 ofabout 317 ng·hours/mL or about 322 ng·hours/mL.

When administered QD (once-daily) to the adult subject, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a mean C_(min,ss) forCompound 1 of from about 2.8 to about 3.2 ng/mL. When administered QD(once-daily) to the adult subject, in certain embodiments, the Compound1 (freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate achieve a mean C_(min,ss) for Compound 1 of fromabout 2.8 to about 3.1 ng/mL, or from about 2.8 to about 3.0 ng/mL, orfrom about 2.8 to about 2.9 ng/mL, or from about 2.9 to about 3.2 ng/mL,or from about 2.9 to about 3.0 ng/mL, or from about 3.0 to about 3.2ng/mL, or from about 3.0 to about 3.1 ng/mL, or from about 3.1 to about3.2 ng/mL. When administered QD (once-daily) to the adult subject, incertain embodiments, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate achieve a meanC_(min,ss) for Compound 1 of about 2.8 ng/mL or about 3.0 ng/mL, orabout 3.1 ng/mL.

When administered QD (once-daily) to the adult subject, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a mean C_(24,ss) forCompound 1 of from about 2.9 to about 3.2 hours. When administered QD(once-daily) to the adult subject under fasting conditions, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a mean C_(24,ss) forCompound 1 of about 3.1 ng/mL. When administered QD (once-daily) to theadult subject under non-fasting conditions, in certain embodiments, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a mean C_(24,ss) for Compound 1 of about3.2 ng/mL.

When administered QD (once-daily) to the adult subject, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a harmonic meant_(1/2,ss) for Compound 1 of from about 9.4 to about 10.5 hours. Whenadministered QD (once-daily) to the adult subject, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a harmonic meant_(1/2,ss) for Compound 1 of from about 9.4 to about 10.4 hours, or fromabout 9.4 to about 10.3 hours, or from about 9.4 to about 10.1 hours, orfrom about 9.4 to about 9.9 hours, or from about 9.5 to about 10.4hours. When administered QD (once-daily) to the adult subject, incertain embodiments, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate achieve a harmonicmean t_(1/2,ss) for Compound 1 of from about 9.4 to about 9.8 hours, orfrom about 9.6 to about 10.0 hours, or from about 9.8 to about 10.2hours, or from about 10.0 to about 10.4 hours, or from about 10.1 toabout 10.5 hours. When administered QD (once-daily) to the adultsubject, in certain embodiments, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a harmonic mean t_(1/2,ss) for Compound 1 of about 10.3 hours orabout 9.4 hours or about 9.5 hours.

In certain embodiments, when administered to the adult subject, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate provides: (a) a mean C_(max) for Compound 1 offrom about 25 to about 70 ng/mL; (b) a T_(max) for Compound 1 of fromabout 1.0 hours to about 6.0 hours; (c) a harmonic mean t_(1/2) forCompound 1 of from about 10.0 to about 14.0 hours; (d) a mean AUC_(inf)for Compound 1 of from about 220 to about 450 ng-hours/mL; (e) a meanC_(max,ss) for Compound 1 of from about 27 to about 55 ng/mL; (f) a meanAUC_(24,ss) for Compound 1 of from about 240 to about 325 ng-hours/mL;(g) a T_(max,ss) for Compound 1 of from about 1.5 to about 6.0 hours;(h) a mean C_(min,ss) for Compound 1 of from about 2.8 to about 3.2ng/mL; (i) a harmonic mean t_(1/2,ss) for Compound 1 of from about 9.4to about 10.5 hours; or combinations thereof.

In certain embodiments, when administered to the adult subject, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate provides: (a) a mean C_(max) for Compound 1 offrom about 25 to about 70 ng/mL; (b) a T_(max) for Compound 1 of fromabout 1.0 hours to about 6.0 hours; (c) a harmonic mean t_(1/2) forCompound 1 of from about 10.0 to about 14.0 hours; (d) a mean AUC_(inf)for Compound 1 of from about 220 to about 450 ng-hours/mL; orcombinations thereof, after a single 15 mg dose.

In certain embodiments, when administered QD (once daily) to the adultsubject, the Compound 1 (freebase) or a pharmaceutically acceptable saltthereof or the crystalline hydrate provides: (a) a mean C_(max,ss) forCompound 1 of from about 27 to about 55 ng/mL; (b) a mean AUC_(24,ss)for Compound 1 of from about 240 to about 325 ng-hours/mL; (c) aT_(max,ss) for Compound 1 of from about 1.5 to about 6.0 hours; (d) amean C_(min,ss) for Compound 1 of from about 2.8 to about 3.2 ng/mL; (e)a harmonic mean t_(1/2,ss) for Compound 1 of from about 9.4 to about10.5 hours; or combinations thereof.

In certain embodiments, when administered to the adult subject underfasting conditions, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate provides: (a) a meanC_(max) for Compound 1 of about 26 ng/mL or about 32 ng/mL; (b) aT_(max) for Compound 1 of from about 1.0 to about 4.0 hours, or fromabout 1.5 to about 6.0 hours, or a median T_(max) for Compound 1 ofabout 3.0 hours; (c) a harmonic mean t_(1/2) for Compound 1 of about12.5 hours; (d) a mean AUC_(inf) for Compound 1 of about 242ng·hours/mL; or combinations thereof, after a single 15 mg dose.

In certain embodiments, when administered to the adult subject undernon-fasting conditions, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate provides: (a) a meanC_(max) for Compound 1 of about 40 ng/mL; (b) a T_(max) for Compound 1of from about 3.0 to about 6.0 hours, or a median T_(max) for Compound 1of about 4.0 hours; (c) a harmonic mean t_(1/2) for Compound 1 of about12.5 hours; or combinations thereof, after a single 15 mg dose.

In certain embodiments, when administered QD (once daily) to the adultsubject under fasting conditions, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydratealternately or additionally may provide (a) a mean C_(max,ss) forCompound 1 of about 32 ng/mL; (b) a mean AUC_(24,ss) for Compound 1 ofabout 279 ng-hours/mL; (c) a T_(max,ss) for Compound 1 of about 1.5 toabout 4.0 hours, or a median T_(max,ss) for Compound 1 of about 2.5hours; (d) a mean C_(min,ss) for Compound 1 of about 3.0 ng/mL or about3.1 ng/mL; (e) a harmonic mean t_(1/2,ss) for Compound 1 of about 9.5hours or about 10.3 hours; or combinations thereof.

In certain embodiments, when administered QD (once daily) to the adultsubject under non-fasting conditions, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydratealternately or additionally may provide (a) a mean C_(max,ss) forCompound 1 of about 36 ng/mL or about 37 ng/mL; (b) a mean AUC_(24,ss)for Compound 1 of about 317 ng·hours/mL or about 322 ng·hours/mL; (c) aT_(max,ss) for Compound 1 of about 2.0 to about 6.0 hours or a medianT_(max,ss) for Compound 1 of about 4.0 hours; (d) a mean C_(min,ss) forCompound 1 of about 2.8 ng/mL or about 3.0 ng/mL; (e) a harmonic meant_(1/2,ss) for Compound 1 of about 9.4 hours or about 9.5 hours or 10.3hours; or combinations thereof.

In certain embodiments, the present disclosure is directed topharmaceutical compositions comprising a crystalline hydrate of Compound1 in an amount sufficient to deliver to the subject 15 mg of Compound 1freebase equivalent. In certain embodiments, the crystalline hydrate isFreebase Hydrate Form C. In one embodiment, the crystalline hydrate isin a once daily extended release formulation. In one embodiment, uponoral administration of the pharmaceutical composition to an adultsubject, the composition provides (a) a mean C_(max) for Compound 1 offrom about 25 to about 70 ng/mL; (b) a T_(max) for Compound 1 of fromabout 1.0 hours to about 6.0 hours; (c) a harmonic mean t_(1/2) forCompound 1 of from about 10.0 to about 14.0 hours; (d) a mean AUC_(inf)for Compound 1 of from about 220 to about 450 ng-hours/mL; (e) a meanC_(max,ss) for Compound 1 of from about 27 to about 55 ng/mL; (f) a meanAUC_(24,ss) for Compound 1 of from about 240 to about 325 ng-hours/mL;(g) a T_(max,ss) for Compound 1 of from about 1.5 to about 6.0 hours;(h) a mean C_(min,ss) for Compound 1 of from about 2.8 to about 3.2ng/mL; (i) a harmonic mean t_(1/2,ss) for Compound 1 of from about 9.4to about 10.5 hours; or combinations thereof.

In one embodiment, upon oral administration of the pharmaceuticalcomposition to an adult subject, the composition provides (a) a meanC_(max) for Compound 1 of from about 25 to about 70 ng/mL; (b) a T_(max)for Compound 1 of from about 1.0 hours to about 6.0 hours; (c) aharmonic mean t_(1/2) for Compound 1 of from about 10.0 to about 14.0hours; (d) a mean AUC_(inf) for Compound 1 of from about 220 to about450 ng-hours/mL; or combinations thereof, after a single 15 mg dose.

In one embodiment, when administered QD (once daily) to the adultsubject the pharmaceutical composition provides (a) a mean C_(max,ss)for Compound 1 of from about 27 to about 55 ng/mL; (b) a meanAUC_(24,ss) for Compound 1 of from about 240 to about 325 ng-hours/mL;(c) a T_(max,ss) for Compound 1 of from about 1.5 to about 6.0 hours;(d) a mean C_(min,ss) for Compound 1 of from about 2.8 to about 3.2ng/mL; (e) a harmonic mean t_(1/2,ss) for Compound 1 of from about 9.4to about 10.5 hours; or combinations thereof.

In one embodiment, upon oral administration of the pharmaceuticalcomposition to an adult subject under fasting conditions, thepharmaceutical composition provides (a) a mean C_(max) for Compound 1 ofabout 26. ng/mL or about 32 ng/mL; (b) a T_(max) for Compound 1 of fromabout 1.0 to about 4.0 hours, or from about 1.5 to about 6.0 hours, or amedian T_(max) for Compound 1 of about 3.0 hours; (c) a harmonic meant_(1/2) for Compound 1 of about 12.5 hours; (d) a mean AUC_(inf) forCompound 1 of about 242 ng·hours/mL; or combinations thereof, after asingle 15 mg dose. In one embodiment, upon oral administration of thepharmaceutical composition to an adult subject under non-fastingconditions, the composition provides (a) a mean C_(max) for Compound 1of about 40 ng/mL; (b) a T_(max) for Compound 1 of from about 3.0 toabout 6.0 hours, or a median T_(max) for Compound 1 of about 4.0 hours;(c) a harmonic mean t_(1/2) for Compound 1 of about 12.5 hours; orcombinations thereof, after a single 15 mg dose.

In one embodiment, upon oral administration of the pharmaceuticalcomposition to an adult subject QD (once daily) under fastingconditions, the composition alternately or additionally provides (a) amean C_(max,ss) for Compound 1 of about 32 ng/mL; (b) a mean AUC_(24,ss)for Compound 1 of about 279 ng-hours/mL; (c) a T_(max,ss) for Compound 1of about 1.5 to about 4.0 hours, or a median T_(max,ss) for Compound 1of about 2.5 hours; (d) a mean C_(min,ss) for Compound 1 of about 3.0ng/mL or about 3.1 ng/mL; (e) a harmonic mean t_(1/2,ss) for Compound 1of about 9.5 hours or about 10.3 hours; or combinations thereof. In oneembodiment, upon oral administration of the pharmaceutical compositionto an adult subject QD (once daily) under non-fasting conditions, thecomposition alternately or additionally provides (a) a mean C_(max,ss)for Compound 1 of about 36 ng/mL or about 37 ng/mL; (b) a meanAUC_(24,ss) for Compound 1 of about 317 ng-hours/mL or about 322ng-hours/mL; (c) a T_(max,ss) for Compound 1 of about 2.0 to about 6.0hours or a median T_(max,ss) for Compound 1 of about 4.0; (d) a meanC_(min,ss) for Compound 1 of about 2.8 ng/mL or about 3.0 ng/mL; (e) aharmonic mean t_(1/2,ss) for Compound 1 of about 9.4 hours or about 9.5hours or about 10.3 hours; or combinations thereof.

In one embodiment, the present disclosure is directed to pharmaceuticalcomposition comprising about 15 mg of Freebase Hydrate Form C, apharmaceutically acceptable carrier, and from about 10 w/w % to about 35w/w % of tartaric acid, wherein the pharmaceutical composition is a oncedaily extended release dosage form (e.g., tablet or capsule) and, uponoral administration of the pharmaceutical composition to an adultsubject, the composition provides (a) a mean C_(max) for Compound 1 offrom about 25 to about 70 ng/mL; (b) a T_(max) for Compound 1 of fromabout 1.0 hours to about 6.0 hours; (c) a harmonic mean t_(1/2) forCompound 1 of from about 10.0 to about 14.0 hours; (d) a mean AUC_(inf)for Compound 1 of from about 220 to about 450 ng-hours/mL; (e) a meanC_(max,ss) for Compound 1 of from about 27 to about 55 ng/mL; (f) a meanAUC_(24,ss) for Compound 1 of from about 240 to about 325 ng-hours/mL;(g) a T_(max,ss) for Compound 1 of from about 1.5 to about 6.0 hours;(h) a mean C_(min,ss) for Compound 1 of from about 2.8 to about 3.2ng/mL; (i) a harmonic mean t_(1/2,ss) for Compound 1 of from about 9.4to about 10.5 hours; or combinations thereof.

In one embodiment, the present disclosure is directed to pharmaceuticalcomposition comprising about 15 mg of Freebase Hydrate Form C, apharmaceutically acceptable carrier, and about 10 w/w % or about 20 w/w% or about 30 w/w % of tartaric acid, wherein the pharmaceuticalcomposition is a once daily extended release dosage form (e.g., tabletor capsule) and, upon oral administration of the pharmaceuticalcomposition to an adult subject, the composition provides (a) a meanC_(max) for Compound 1 of from about 25 to about 70 ng/mL; (b) a T_(max)for Compound 1 of from about 1.0 hours to about 6.0 hours; (c) aharmonic mean t_(1/2) for Compound 1 of from about 10.0 to about 14.0hours; (d) a mean AUC_(inf) for Compound 1 of from about 220 to about450 ng-hours/mL; or combinations thereof after a single 15 mg dose.

In one embodiment, the present disclosure is directed to pharmaceuticalcomposition comprising about 15 mg of Freebase Hydrate Form C, apharmaceutically acceptable carrier, and about 10 w/w % or about 20 w/w% or about 30 w/w % of tartaric acid, wherein the pharmaceuticalcomposition is a once daily extended release dosage form (e.g., tabletor capsule) and, upon oral administration of the pharmaceuticalcomposition to an adult subject QD (once daily), the compositionprovides (a) a mean C_(max,ss) for Compound 1 of from about 27 to about55 ng/mL; (b) a mean AUC_(24,ss) for Compound 1 of from about 240 toabout 325 ng-hours/mL; (c) a T_(max,ss) for Compound 1 of from about 1.5to about 6.0 hours; (d) a mean C_(min,ss) for Compound 1 of from about2.8 to about 3.2 ng/mL; (e) a harmonic mean t_(1/2,ss) for Compound 1 offrom about 9.4 to about 10.5 hours; or combinations thereof.

30 mg Dosage Formulations

In certain embodiments, the methods of the present disclosure compriseadministering to an adult subject (e.g., a human subject) 30 mg ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora crystalline hydrate of Compound 1 in an amount sufficient to deliverto the subject 30 mg of Compound 1 freebase equivalent. In oneembodiment, the freebase or the hydrate is in a once daily extendedrelease formulation.

Unless otherwise indicated, the following pharmacokinetic parameters areachieved after administration of a single 30 mg dose the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate (e.g., Freebase Hydrate Form C) to the adultsubject, or after administration of a sufficient number of once-daily 30mg doses to achieve a steady-state. By a single 30 mg dose, it is meanta single dosage unit containing an amount of freebase orpharmaceutically acceptable salt or crystalline hydrate sufficient todeliver to the subject 30 mg of Compound 1 freebase equivalent. In oneembodiment, the single dosage unit is a once daily extended releaseformulation.

In certain embodiments, when administered to the adult subject, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a mean C_(max) for Compound 1 of fromabout 55 to about 85 ng/mL after a single 30 mg dose. In certainembodiments, when administered to the adult subject, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate achieve a mean C_(max) for Compound 1 of from about55 to about 70 ng/mL, or from about 55 to about 67 ng/mL, or from about55 to about 66 ng/mL, or from about 70 to about 85 ng/mL, or from about72 to about 85 ng/mL, or from about 74 to about 85 ng/mL, after a single30 mg dose.

In certain embodiments, when administered to the subject under fastingconditions, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a mean C_(max) forCompound 1 of from about 55 ng/mL to about 66 ng/mL, or about 55 ng/mL,or about 56 ng/mL, or about 57 ng/mL, or about 59 ng/mL, or about 61ng/mL, or about 64 ng/mL, or about 66 ng/mL after a single 30 mg dose.In other embodiments, when administered to the subject under non-fastingconditions, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a mean C_(max) forCompound 1 of from about 74 ng/mL to about 85 ng/mL, or about 74 ng/mL,or about 76 ng/mL, or about 77 ng/mL, or about 79 ng/mL, about 82 ng/mL,or about 84 ng/mL after a single 30 mg dose.

In certain embodiments, when the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrate isadministered to the subject, the difference in the C_(max) for Compound1 after a 30 mg dose in the fed versus the fasted state is about 55% orless, or about 53% or less, or about 30% or less, or about 20% or less,or about 10% or less. In one embodiment, the difference in the C_(max)for Compound 1 after a 30 mg dose in the fed versus the fasted state isfrom about 3% to about 40%, or from about 15% to about 55%.

When administered to the adult subject, in certain embodiments, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a T_(max) for Compound 1 from about 1.0to about 8.0 hours after a single 30 mg dose. When administered to theadult subject, in certain embodiments, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a T_(max) for Compound 1 from about 2.0 to about 6.0 hours, orfrom about 1.0 to about 4.0 hours, or from about 1.5 to about 4.0 hours,or from about 1.5 to about 8.0 hours, or from about 2.0 to about 4.0hours, or from about 2.0 to about 3.0 hours, after a single 30 mg dose.

In other embodiments, when administered to the adult subject underfasting conditions, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate achieve a T_(max) forCompound 1 of from about 1.0 to about 4.0 hours, or from about 1.5 toabout 4.0 hours, or a median T_(max) for Compound 1 of about 2.0 hours,or about 2.5 hours, or about 3.0 hours after a single 30 mg dose. Inother embodiments, when administered to the adult subject undernon-fasting conditions, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate achieve a T_(max) forCompound 1 of from about 1.5 to about 8.0 hours, or about 2.0 to about6.0 hours, or a median T_(max) for Compound 1 of about 4.0 hours after asingle 30 mg dose.

When administered to the adult subject, in certain embodiments, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a harmonic mean t_(1/2) for Compound 1of from about 9.0 to about 12.0 hours after a single 30 mg dose. Whenadministered to the adult subject, in certain embodiments, the Compound1 (freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate achieve a harmonic mean t_(1/2) for Compound 1 offrom about 9.0 to about 11.0 hours, or from about 9.0 to about 10.0hours, or from about 10.0 to about 12.0 hours, or from about 10.0 toabout 11.5 hours, after a single 30 mg dose.

When administered to the adult subject, in certain embodiments, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a harmonic mean t_(1/2) for Compound 1of about 9.0 hours, or about 9.5 hours, or about 10.0 hours, or about10.5 hours, or about 11.0 hours, or about 11.5 hours, or about 12.0hours, after a single 30 mg dose.

When administered to the adult subject, in certain embodiments, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a mean AUC_(inf) for Compound 1 of fromabout 453 to about 660 ng·hours/mL after a single 30 mg dose. Whenadministered to the adult subject, in certain embodiments, the Compound1 (freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate achieve a mean AUC_(inf) for Compound 1 of fromabout 483 to about 660 ng·hours/mL, from about 483 to about 550ng·hours/mL, or from about 484 to about 515 ng·hours/mL, or from about484 to about 513 ng·hours/mL, or from about 560 to about 660ng·hours/mL, or from about 570 to about 660 ng·hours/mL, or from about577 to about 657 ng·hours/mL, after a single 30 mg dose.

When administered to the adult subject under fasting conditions, incertain embodiments, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate achieve a meanAUC_(inf) for Compound 1 of from about 484 to about 550 ng·hours/mL, orabout 484 ng·hours/mL, or about 491 ng·hours/mL, or about 495ng·hours/mL, or about 499 ng·hours/mL, or about 513 ng·hours/mL after asingle 30 mg dose. When administered to the adult subject under fastingconditions, in certain embodiments, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a mean AUC_(t) for Compound 1 of about 473 ng·hours/mL, or about477 ng·hours/mL, about 481 ng·hours/mL, or about 487 ng·hours/mL, orabout 495 ng·hours/mL, or a mean AUC₂₄ of about 454 ng·hours/mL, after asingle 30 mg dose. When administered to the adult subject undernon-fasting conditions, in certain embodiments, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate achieve a mean AUC_(inf) for Compound 1 of fromabout 560 to about 660 ng·hours/mL, or about 577 ng·hours/mL, or about609 ng·hours/mL, or about 622 ng·hours/mL, or about 657 ng·hours/mL,after a single 30 mg dose. When administered to the adult subject undernon-fasting conditions, in certain embodiments, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate achieve a mean AUC₂₄ for Compound 1 of about 517ng·hours/mL or about 563 ng·hours/mL, or a mean AUC_(t) of about 564ng·hours/mL, or about 605 ng·hours/mL, or about 615 ng·hours/mL, orabout 648 ng·hours/mL, after a single 30 mg dose.

In certain embodiments, when the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrate isadministered to the subject, the difference in the AUC_(inf) forCompound 1 after a 30 mg dose in the fed versus the fasted state isabout 30% or less, or about 20% or less, or about 10% or less.

When administered to the adult subject, in certain embodiments, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a mean C₂₄ for Compound 1 of from about2.3 to about 4.5 ng/mL after a single 30 mg dose. When administered tothe adult subject under fasting conditions, in certain embodiments, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a mean C₂₄ for Compound 1 of about 2.7ng/mL, or about 3.2 ng/mL, or about 2.8 ng/mL, or about 3.5 ng/mL, orabout 3.7 ng/mL, or about 3.9 ng/mL, after a single 30 mg dose. Whenadministered to the adult subject under non-fasting conditions, incertain embodiments, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate achieve a mean C₂₄for Compound 1 of about 2.4 ng/mL, or about 2.6 ng/mL, or about 2.8ng/mL, or about 2.9 ng/mL, or about 4.3 ng/mL, after a single 30 mgdose.

When administered QD (once daily) to the adult subject, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a mean C_(max,ss) forCompound 1 of from about 65 to about 86 ng/mL. When administered QD(once daily) to the adult subject, in certain embodiments, the Compound1 (freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate achieve a mean C_(max,ss) for Compound 1 of fromabout 65 to about 70 ng/mL, or from about 67 to about 68 ng/mL, or fromabout 78 to about 86 ng/mL, or from about 80 to about 84 ng/mL.

When administered QD (once daily) to the adult subject under fastingconditions, in certain embodiments, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a mean C_(max,ss) for Compound 1 of about 67 ng/mL or about 68ng/mL. When administered QD (once daily) to the adult subject undernon-fasting conditions, in certain embodiments, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate achieve a mean C_(max,ss) for Compound 1 of about 80ng/mL or about 84 ng/mL.

When administered QD (once-daily) to the adult subject, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a T_(max,ss) of fromabout 1.5 to about 6.0 hours. When administered QD (once-daily) to theadult subject, in certain embodiments, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a T_(max,ss) of from about 1.5 to about 4.0 hours, or from about2.0 to about 4.0 hours, or from about 3.0 to about 4.0 hours, or fromabout 3.5 to about 4.0 hours.

When administered QD (once-daily) to the adult subject under fastingconditions, in certain embodiments, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a T_(max,ss) of from about 2.0 to about 4.0 hours, or a medianT_(max,ss) for Compound 1 of about 3.0 hours. When administered QD(once-daily) to the adult subject under non-fasting conditions, incertain embodiments, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate achieve a T_(max,ss)of from about 1.5 to about 6.0 hours, or a median T_(max,ss) forCompound 1 of about 3.5 hours or about 4.0 hours.

When administered QD (once daily) to the adult subject, in certainembodiments, the Compound 1 (freebase) or the crystalline hydrateachieve a mean C_(trough) for Compound 1 of from about 2.8 to about 6.1ng/mL. When administered QD (once daily) to the adult subject underfasting conditions, in certain embodiments, the Compound 1 (freebase) orthe crystalline hydrate achieve a mean C_(trough) for Compound 1 ofabout 4.9 ng/mL. When administered QD (once daily) to the adult subjectunder non-fasting conditions, in certain embodiments, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate achieve a mean C_(trough) for Compound 1 of fromabout 2.8 to about 6.1 ng/mL, or from about 4.6 to about 6.1 ng/mL, orabout 3.0 ng/mL, or about 4.7 ng/mL or about 5.3 ng/mL or about 6.1ng/mL.

When administered QD (once daily) to the adult subject, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a mean AUC_(24,ss) forCompound 1 of from about 485 to about 658 ng·hours/mL. When administeredQD (once daily) to the adult subject, in certain embodiments, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate achieve a mean AUC_(24,ss) for Compound 1 offrom about 520 to about 640 ng·hours/mL, or from about 520 to about 630ng·hours/mL, or from about 525 to about 620 ng·hours/mL, or from about525 to about 585 ng·hours/mL, or from about 580 to about 630ng·hours/mL, or from about 582 to about 620 ng·hours/mL.

When administered to the adult subject under fasting conditions, incertain embodiments, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate achieve a meanAUC_(24,ss) for Compound 1 of about 525 ng·hours/mL. When administeredto the adult subject under non-fasting conditions, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a mean AUC_(24,ss) forCompound 1 of about 582 ng·hours/mL or about 620 ng·hours/mL.

When administered QD (once-daily) to the adult subject, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a mean C_(min,ss) forCompound 1 of from about 3.5 to about 5.3 ng/mL. When administered QD(once-daily) to the adult subject, in certain embodiments, the Compound1 (freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate achieve a mean C_(min,ss) for Compound 1 of fromabout 3.6 to about 5.2 ng/mL, or from about 3.8 to about 5.2 ng/mL, orfrom about 4.6 to about 5.2 ng/mL.

When administered QD (once-daily) to the adult subject under fastingconditions, in certain embodiments, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a mean C_(min,ss) for Compound 1 of about 3.8 ng/mL. Whenadministered QD (once-daily) to the adult subject under non-fastingconditions, in certain embodiments, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a mean C_(min,ss) for Compound 1 of about 4.6 ng/mL or about 5.2ng/mL.

When administered QD (once-daily) to the adult subject, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a mean C_(24,ss) forCompound 1 of from about 4.0 to about 5.3 hours. When administered QD(once-daily) to the adult subject under fasting conditions, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a mean C_(24,ss) forCompound 1 of about 4.3 ng/mL or about 4.4 ng/mL. When administered QD(once-daily) to the adult subject under non-fasting conditions, incertain embodiments, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate achieve a meanC_(24,ss) for Compound 1 of about 5.3 ng/mL.

When administered QD (once-daily) to the adult subject, in certainembodiments, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate achieve a harmonic meant_(1/2,ss) for Compound 1 of from about 10.0 to about 14.5 hours. Whenadministered QD (once-daily) to the adult subject, in certainembodiments, the Compound 1 (freebase) or the crystalline hydrateachieve a harmonic mean t_(1/2,ss) for Compound 1 of from about 10.1 toabout 14.4 hours, or from about 10.1 to about 10.4 hours, or from about10.4 hours to about 14.4 hours. When administered QD (once-daily) to theadult subject, in certain embodiments, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrateachieve a harmonic mean t_(1/2,ss) for Compound 1 of about 14.4 hours orabout 10.1 hours or about 10.4 hours.

In certain embodiments, when administered to the adult subject, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate provides: (a) a mean C_(max) for Compound 1 offrom about 55 to about 85 ng/mL; (b) a T_(max) for Compound 1 of fromabout 1.0 hours to about 8.0 hours; (c) a harmonic mean t_(1/2) forCompound 1 of from about 9.0 to about 12.0 hours; (d) a mean AUC_(inf)for Compound 1 of from about 483 to about 660 ng-hours/mL; (e) a meanC_(max,ss) for Compound 1 of from about 65 to about 85 ng/mL; (f) a meanAUC_(24,ss) for Compound 1 of from about 485 to about 658 ng-hours/mL;(g) a T_(max,ss) for Compound 1 of from about 1.5 to about 6.0 hours;(h) a mean C_(min,ss) for Compound 1 of from about 3.5 to about 5.3ng/mL; (i) a harmonic mean t_(1/2,ss) for Compound 1 of from about 10.0to about 14.5 hours; or combinations thereof.

In certain embodiments, when administered to the adult subject, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe crystalline hydrate provides: (a) a mean C_(max) for Compound 1 offrom about 55 to about 85 ng/mL; (b) a T_(max) for Compound 1 of fromabout 1.0 hours to about 8.0 hours; (c) a harmonic mean t_(1/2) forCompound 1 of from about 9.0 to about 12.0 hours; (d) a mean AUC_(inf)for Compound 1 of from about 483 to about 660 ng-hours/mL; orcombinations thereof, after a single 30 mg dose.

In certain embodiments, when administered QD (once-daily) to the adultsubject, the Compound 1 (freebase) or a pharmaceutically acceptable saltthereof or the crystalline hydrate provides: (a) a mean C_(max,ss) forCompound 1 of from about 65 to about 85 ng/mL; (b) a mean AUC_(24,ss)for Compound 1 of from about 485 to about 658 ng-hours/mL; (c) aT_(max,ss) for Compound 1 of from about 1.5 to about 6.0 hours; (d) amean C_(min,ss) for Compound 1 of from about 3.5 to about 5.3 ng/mL; (e)a harmonic mean t_(1/2,ss) for Compound 1 of from about 10.0 to about14.5 hours; or combinations thereof.

In certain embodiments, when administered to the adult subject underfasting conditions, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate provides: (a) a meanC_(max) for Compound 1 of from about 55 ng/mL to about 66 ng/mL, orabout 55 ng/mL, or about 56 ng/mL, or about 57 ng/mL, or about 59 ng/mL,or about 61 ng/mL, or about 64 ng/mL or about 66 ng/mL; (b) a T_(max)for Compound 1 of from about 1.0 hours to about 4.0 hours, or about 1.5hours to about 4.0 hours, or a median T_(max) for Compound 1 of about2.0 hours, or about 2.5 hours, or about 3.0 hours; (c) a harmonic meant_(1/2) for Compound 1 of about 9.0 hours, or about 9.5 hours, or about10.0 hours, or about 10.5 hours, or about 11.0 hours, or about 11.5hours, or about 12.0 hours; (d) a mean AUC_(inf) for Compound 1 of about484 to about 550 ng·hours/mL, or about 484 ng·hours/mL, or about 491ng·hours/mL, or about 495 ng·hours/mL, or about 499 ng·hours/mL, orabout 513 ng·hours/mL; or combinations thereof, after a single 30 mgdose.

In certain embodiments, when administered to the adult subject undernon-fasting conditions, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate provides (a) a meanC_(max) for Compound 1 of from about 76 ng/mL to about 85 ng/mL, orabout 76 ng/mL, or about 77 ng/mL, or about 79 ng/mL, about 82 ng/mL, orabout 84 ng/mL; (b) a T_(max) for Compound 1 of from about 1.5 hours toabout 8.0 hours, or from about 2.0 hours to about 6.0 hours, or a medianT_(max) for Compound 1 of about 4.0 hours; (c) a harmonic mean t_(1/2)for Compound 1 of about 9.0 hours, or about 9.5 hours, or about 10.0hours, or about 10.5 hours, or about 11.0 hours, or about 11.5 hours, orabout 12.0 hours; (d) a mean AUC_(inf) for Compound 1 of about 577ng·hours/mL, or about 609 ng·hours/mL, or about 622 ng·hours/mL, orabout 657 ng·hours/mL; or combinations thereof, after a single 30 mgdose.

In one embodiment, when administered QD (once daily) to the adultsubject under fasting conditions, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydratealternately or additionally provides (a) a mean C_(max,ss) for Compound1 of about 67 ng/mL or about 68 ng/mL; (b) a mean AUC_(24,ss) forCompound 1 of about 525 ng·hours/mL; (c) a T_(max,ss) for Compound 1 offrom about 2.0 to about 4.0 hours, or a median T_(max,ss) for Compound 1of about 3.0 hours; (d) a mean C_(min,ss) for Compound 1 of about 3.8ng/mL; (e) a harmonic mean t_(1/2,ss) for Compound 1 of about 10.1 hoursor about 10.4 hours or about 14.4 hours; or combinations thereof.

In one embodiment, when administered QD (once daily) to the adultsubject under non-fasting conditions, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydratealternately or additionally provides (a) a mean C_(max,ss) for Compound1 of about 80 ng/mL or about 84 ng/mL; (b) a mean AUC_(24,ss) forCompound 1 of about 582 ng·hours/mL or about 620 ng·hours/mL; (c) aT_(max,ss) for Compound 1 of from about 1.5 to about 6.0 hours or amedian T_(max,ss) for Compound 1 of about 3.5 hours or about 4.0 hours;(d) a C_(min,ss) for Compound 1 of about 4.6 ng/mL or about 5.2 ng/mL;(e) a harmonic mean t_(1/2,ss) for Compound 1 of about 10.1 hours orabout 10.4 hours or about 14.4 hours; or combinations thereof.

In certain embodiments, the present disclosure is directed topharmaceutical compositions comprising a crystalline hydrate of Compound1 in an amount sufficient to deliver to the subject 30 mg of Compound 1freebase equivalent. In certain embodiments, the crystalline hydrate isFreebase Hydrate Form C. In one embodiment, the crystalline hydrate isin a once daily extended release formulation. In one embodiment, uponoral administration of the pharmaceutical composition to an adultsubject, the composition provides (a) a mean C_(max) for Compound 1 offrom about 55 to about 85 ng/mL; (b) a T_(max) for Compound 1 of fromabout 1.0 hours to about 8.0 hours; (c) a harmonic mean t_(1/2) forCompound 1 of from about 9.0 to about 12.0 hours; (d) a mean AUC_(inf)for Compound 1 of from about 483 to about 660 ng-hours/mL; (e) a meanC_(max,ss) for Compound 1 of from about 65 to about 85 ng/mL; (f) a meanAUC_(24,ss) for Compound 1 of from about 485 to about 658 ng-hours/mL;(g) a T_(max,ss) for Compound 1 of from about 1.5 to about 6.0 hours;(h) a mean C_(min,ss) for Compound 1 of from about 3.5 to about 5.3ng/mL; (i) a harmonic mean t_(1/2,ss) for Compound 1 of from about 10.0to about 14.5 hours; or combinations thereof.

In one embodiment, upon oral administration of the pharmaceuticalcomposition to an adult subject, the composition provides (a) a meanC_(max) for Compound 1 of from about 55 to about 85 ng/mL; (b) a T_(max)for Compound 1 of from about 1.0 hours to about 8.0 hours; (c) aharmonic mean t_(1/2) for Compound 1 of from about 9.0 to about 12.0hours; (d) a mean AUC_(inf) for Compound 1 of from about 483 to about660 ng-hours/mL; or combinations thereof, after a single 30 mg dose.

In one embodiment, upon oral administration of the pharmaceuticalcomposition to an adult subject QD (once daily), the compositionprovides (a) a mean C_(max,ss) for Compound 1 of from about 65 to about85 ng/mL; (b) a mean AUC_(24,ss) for Compound 1 of from about 485 toabout 658 ng-hours/mL; (c) a T_(max,ss) for Compound 1 of from about 1.5to about 6.0 hours; (d) a mean C_(min,ss) for Compound 1 of from about3.5 to about 5.3 ng/mL; (e) a harmonic mean t_(1/2,ss) for Compound 1 offrom about 10.0 to about 14.5 hours; or combinations thereof.

In one embodiment, upon oral administration of the pharmaceuticalcomposition to an adult subject under fasting conditions, thecomposition provides (a) a mean C_(max) for Compound 1 of from about 55ng/mL to about 66 ng/mL, or about 55 ng/mL, or about 56 ng/mL, or about57 ng/mL, or about 59 ng/mL, or about 61 ng/mL, or about 64 ng/mL orabout 66 ng/mL; (b) a T_(max) for Compound 1 of from about 1.0 hours toabout 4.0 hours, or from about 1.5 hours to about 4.0 hours, or a medianT_(max) for Compound 1 of about 2.0 hours, or about 2.5 hours, or about3.0 hours; (c) a harmonic mean t_(1/2) for Compound 1 of about 9.0hours, or about 9.5 hours, or about 10.0 hours, or about 10.5 hours, orabout 11.0 hours, or about 11.5 hours, or about 12.0 hours; (d) a meanAUC_(inf) for Compound 1 of about 484 to about 550 ng·hours/mL, or about484 ng·hours/mL, or about 491 ng·hours/mL, or about 495 ng·hours/mL, orabout 499 ng·hours/mL, or about 513 ng·hours/mL; or combinationsthereof, after a single 30 mg dose.

In one embodiment, upon oral administration of the pharmaceuticalcomposition to an adult subject under non-fasting conditions, thecomposition provides (a) a mean C_(max) for Compound 1 of from about 76ng/mL to about 85 ng/mL, or about 76 ng/mL, or about 77 ng/mL, or about79 ng/mL, about 82 ng/mL, or about 84 ng/mL; (b) a T_(max) for Compound1 of from about 1.5 hours to about 8.0 hours, or from about 2.0 hours toabout 6.0 hours, or a median T_(max) for Compound 1 of about 4.0 hours;(c) a harmonic mean t_(1/2) for Compound 1 of about 9.0 hours, or about9.5 hours, or about 10.0 hours, or about 10.5 hours, or about 11.0hours, or about 11.5 hours, or about 12.0 hours; (d) a mean AUC_(inf)for Compound 1 of about 577 ng·hours/mL, or about 609 ng·hours/mL, orabout 622 ng·hours/mL, or about 657 ng·hours/mL; or combinationsthereof, after a single 30 mg dose.

In one embodiment, upon oral administration of the pharmaceuticalcomposition to an adult subject QD (once daily) under fastingconditions, the composition alternately or additionally provides (a) amean C_(max,ss) for Compound 1 of about 67 ng/mL or about 68 ng/mL; (b)a mean AUC_(24,ss) for Compound 1 of about 525 ng·hours/mL; (c) aT_(max,ss) for Compound 1 of from about 2.0 to about 4.0 hours, or amedian T_(max,ss) for Compound 1 of about 3.0 hours; (d) a meanC_(min,ss) for Compound 1 of about 3.8 ng/mL; (e) a harmonic meant_(1/2,ss) for Compound 1 of about 10.1 hours or about 10.4 hours orabout 14.4 hours; or combinations thereof.

In one embodiment, upon oral administration of the pharmaceuticalcomposition to an adult subject QD (once daily) under non-fastingconditions, the composition alternately or additionally provides (a) amean C_(max,ss) for Compound 1 of about 80 ng/mL or about 84 ng/mL; (b)a mean AUC_(24,ss) for Compound 1 of about 582 ng·hours/mL or about 620ng·hours/mL; (c) a T_(max,ss) for Compound 1 of from about 1.5 to about6.0 hours or a median T_(max,ss) for Compound 1 of about 3.5 hours orabout 4.0 hours; (d) a C_(min,ss) for Compound 1 of about 4.6 ng/mL orabout 5.2 ng/mL; (e) a harmonic mean t_(1/2,ss) for Compound 1 of about10.1 hours or about 10.4 hours or about 14.4 hours; or combinationsthereof or combinations thereof.

In one embodiment, the present disclosure is directed to pharmaceuticalcompositions comprising about 30 mg of Freebase Hydrate Form C, apharmaceutically acceptable carrier, and from about 10 w/w % to about 35w/w % of tartaric acid, wherein the pharmaceutical composition is a oncedaily extended release formulation, and wherein upon oral administrationof the pharmaceutical composition to an adult subject, the compositionprovides (a) a mean C_(max) for Compound 1 of from about 55 to about 85ng/mL; (b) a T_(max) for Compound 1 of from about 1.0 hours to about 8.0hours; (c) a harmonic mean t_(1/2) for Compound 1 of from about 9.0 toabout 12.0 hours; (d) a mean AUC_(inf) for Compound 1 of from about 483to about 660 ng-hours/mL; (e) a mean C_(max,ss) for Compound 1 of fromabout 65 to about 85 ng/mL; (f) a mean AUC_(24,ss) for Compound 1 offrom about 485 to about 658 ng-hours/mL; (g) a T_(max,ss) for Compound 1of from about 1.5 to about 6.0 hours; (h) a mean C_(min,ss) for Compound1 of from about 3.5 to about 5.3 ng/mL; (i) a harmonic mean t_(1/2,ss)for Compound 1 of from about 10.0 to about 14.5 hours; or combinationsthereof.

In one embodiment, the present disclosure is directed to pharmaceuticalcompositions comprising about 30 mg of Freebase Hydrate Form C, apharmaceutically acceptable carrier, and about 10 w/w % or about 20 w/w% or about 30 w/w % of tartaric acid, wherein the pharmaceuticalcomposition is a once daily daily extended release formulation, andwherein upon oral administration of the pharmaceutical composition to anadult subject, the composition provides (a) a mean C_(max) for Compound1 of from about 55 to about 85 ng/mL; (b) a T_(max) for Compound 1 offrom about 1.0 hours to about 8.0 hours; (c) a harmonic mean t_(1/2) forCompound 1 of from about 9.0 to about 12.0 hours; (d) a mean AUC_(inf)for Compound 1 of from about 483 to about 660 ng-hours/mL; orcombinations thereof after a single 30 mg dose.

In one embodiment, the present disclosure is directed to pharmaceuticalcompositions comprising about 30 mg of Freebase Hydrate Form C, apharmaceutically acceptable carrier, and about 10 w/w % or about 20 w/w.% or about 30 w/w % of tartaric acid, wherein the pharmaceuticalcomposition is a once daily daily extended release formulation, andwherein upon oral administration of the pharmaceutical composition to anadult subject QD (once daily), the composition provides (a) a meanC_(max,ss) for Compound 1 of from about 65 to about 85 ng/mL; (b) a meanAUC_(24,ss) for Compound 1 of from about 485 to about 658 ng-hours/mL;(c) a T_(max,ss) for Compound 1 of from about 1.5 to about 6.0 hours;(d) a mean C_(min,ss) for Compound 1 of from about 3.5 to about 5.3ng/mL; (e) a harmonic mean t_(1/2,ss) for Compound 1 of from about 10.0to about 14.5 hours; or combinations thereof.

VIII. EXTENDED RELEASE TABLETS

In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate used in the methodsof the present disclosure is in a once daily extended releaseformulation. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrate isin a once daily extended release formulation, and the formulationdelivers about 7.5 mg or about 15 mg or about 30 mg or about 45 mg perunit dosage form (e.g., per tablet or capsule) of Compound 1 (freebaseequivalent) orally QD (once daily). In one particular embodiment, thecrystalline hydrate is Freebase Hydrate Form C.

In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate is in a once dailyextended release formulation, and the formulation delivers 7.5 mg ofCompound 1 (freebase equivalent) orally QD (once daily). In some suchembodiments, the once daily extended release formulation will have arelative bioavailability approximately equivalent to that of animmediate release capsule comprising Compound 1 (freebase) or apharmaceutically acceptable salt thereof or a solid state form thereofthat delivers 3 mg of Compound 1 (freebase equivalent) and that isadministered two times per day (BID). In one embodiment, the immediaterelease capsule comprises a crystalline hydrate of Compound 1. In oneembodiment, the immediate release capsule comprises Freebase HydrateForm C. In one embodiment, the immediate release capsule comprisesTartrate Hydrate.

In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate is in a once dailyextended release formulation, and the formulation delivers 15 mg ofCompound 1 (freebase equivalent) orally QD (once daily). In some suchembodiments, the once daily extended release formulation will have arelative bioavailability approximately equivalent to that of animmediate release capsule comprising Compound 1 (freebase) or apharmaceutically acceptable salt thereof or a solid state form thereofthat delivers 6 mg of Compound 1 (freebase equivalent) and that isadministered two times per day (BID). In one embodiment, the immediaterelease capsule comprises a crystalline hydrate of Compound 1. In oneembodiment, the immediate release capsule comprises Freebase HydrateForm C. In one embodiment, the immediate release capsule comprisesTartrate Hydrate.

In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate is in a once dailyextended release formulation, and the formulation delivers 30 mg ofCompound 1 (freebase equivalent) orally QD (once daily). In some suchembodiments, the once daily extended release formulation will have arelative bioavailability approximately equivalent to that of animmediate release capsule comprising Compound 1 (freebase) or apharmaceutically acceptable salt thereof or a solid state form thereofthat delivers 12 mg of Compound 1 (freebase equivalent) and that isadministered two times per day (BID). In one embodiment, the immediaterelease capsule comprises a crystalline hydrate of Compound 1. In oneembodiment, the immediate release capsule comprises Freebase HydrateForm C. In one embodiment, the immediate release capsule comprisesTartrate Hydrate.

In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate is in a once dailyextended release formulation, and the formulation delivers 45 mg ofCompound 1 (freebase equivalent) orally QD (once daily). In some suchembodiments, the once daily extended release formulation will have arelative bioavailability approximately equivalent to that of animmediate release capsule comprising Compound 1 (freebase) or apharmaceutically acceptable salt thereof or a solid state form thereofthat delivers 18 mg of Compound 1 (freebase equivalent) and that isadministered two times per day (BID). In one embodiment, the immediaterelease capsule comprises a crystalline hydrate of Compound 1. In oneembodiment, the immediate release capsule comprises Freebase HydrateForm C. In one embodiment, the immediate release capsule comprisesTartrate Hydrate.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Compound 1 freebaseor a pharmaceutically acceptable salt thereof or a solid state form ofCompound 1, and a pharmaceutically acceptable carrier, whereinpharmaceutical composition is a once daily extended release formulation,and the solid state form of Compound 1 is selected from the groupconsisting of Amorphous Freebase, Freebase Hydrate Form B, FreebaseHydrate Form C, and Freebase Anhydrate Form D.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Compound 1 freebaseor a pharmaceutically acceptable salt thereof or a solid state form ofCompound 1, a pharmaceutically acceptable carrier, and a pH modifier,wherein the pharmaceutical composition is a once daily extended releaseformulation, and the solid state form of Compound 1 is selected from thegroup consisting of Amorphous Freebase, Freebase Hydrate Form B,Freebase Hydrate Form C, and Freebase Anhydrate Form D. In oneembodiment, the pharmaceutical composition comprises from about 10 wt %to about 30 wt. % of the pH modifier. In one embodiment, the pH modifieris tartaric acid.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of a solid state formof Compound 1, a pharmaceutically acceptable carrier, and from about 10w/w % to about 35 w/w % of tartaric acid, wherein the pharmaceuticalcomposition is a once daily extended release formulation, and the solidstate form of Compound 1 is selected from the group consisting ofAmorphous Freebase, Freebase Hydrate Form B, Freebase Hydrate Form C,and Freebase Anhydrate Form D.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Freebase HydrateForm B, a pharmaceutically acceptable carrier, and from about 10 w/w %to about 35 w/w % of tartaric acid wherein the pharmaceuticalcomposition is a once daily extended release formulation.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Amorphous Freebase,a pharmaceutically acceptable carrier, and from about 10 w/w % to about35 w/w % of tartaric acid wherein the pharmaceutical composition is aonce daily extended release formulation.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Freebase AnhydrateForm D, a pharmaceutically acceptable carrier, and from about 10 w/w %to about 35 w/w % of tartaric acid wherein the pharmaceuticalcomposition is a once daily extended release formulation.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and from about 10 w/w %to about 35 w/w % of tartaric acid wherein the pharmaceuticalcomposition is a once daily extended release formulation.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and about 10 w/w % oftartaric acid, wherein the pharmaceutical composition is a once dailyextended release formulation.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and about 20 w/w % oftartaric acid, wherein the pharmaceutical composition is a once dailyextended release formulation.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 15 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and about 30 w/w % oftartaric acid, wherein the pharmaceutical composition is a once dailyextended release formulation.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Compound 1 freebaseor a pharmaceutically acceptable salt thereof or a solid state form ofCompound 1, and a pharmaceutically acceptable carrier, whereinpharmaceutical composition is a once daily extended release formulation,and the solid state form of Compound 1 is selected from the groupconsisting of Amorphous Freebase, Freebase Hydrate Form B, FreebaseHydrate Form C, and Freebase Anhydrate Form D.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Compound 1 freebaseor a pharmaceutically acceptable salt thereof or a solid state form ofCompound 1, a pharmaceutically acceptable carrier, and a pH modifier,wherein the pharmaceutical composition is a once daily extended releaseformulation, and the solid state form of Compound 1 is selected from thegroup consisting of Amorphous Freebase, Freebase Hydrate Form B,Freebase Hydrate Form C, and Freebase Anhydrate Form D. In oneembodiment, the pharmaceutical composition comprises from about 10 wt %to about 30 wt. % of the pH modifier. In one embodiment, the pH modifieris tartaric acid.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of a solid state formof Compound 1, a pharmaceutically acceptable carrier, and from about 10w/w % to about 35 w/w % of tartaric acid, wherein the pharmaceuticalcomposition is a once daily extended release formulation, and the solidstate form of Compound 1 is selected from the group consisting ofAmorphous Freebase, Freebase Hydrate Form B, Freebase Hydrate Form C,and Freebase Anhydrate Form D.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Freebase HydrateForm B, a pharmaceutically acceptable carrier, and from about 10 w/w %to about 35 w/w % of tartaric acid wherein the pharmaceuticalcomposition is a once daily extended release formulation.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Amorphous Freebase,a pharmaceutically acceptable carrier, and from about 10 w/w % to about35 w/w % of tartaric acid wherein the pharmaceutical composition is aonce daily extended release formulation.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Freebase AnhydrateForm D, a pharmaceutically acceptable carrier, and from about 10 w/w %to about 35 w/w % of tartaric acid wherein the pharmaceuticalcomposition is a once daily extended release formulation.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and from about 10 w/w %to about 35 w/w % of tartaric acid wherein the pharmaceuticalcomposition is a once daily extended release formulation.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and about 10 w/w % oftartaric acid wherein the pharmaceutical composition is a once dailyextended release formulation.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and about 20 w/w % oftartaric acid wherein the pharmaceutical composition is a once dailyextended release formulation.

In one embodiment, the present disclosure is directed to apharmaceutical composition comprising about 30 mg of Freebase HydrateForm C, a pharmaceutically acceptable carrier, and about 30 w/w % oftartaric acid wherein the pharmaceutical composition is a once dailyextended release formulation.

IX. KITS

The present disclosure also relates to kits comprising one or more solidpharmaceutical dosage units (such as tablets or capsules) comprising asolid state form of the present disclosure. The kit optionally cancomprise one or more additional therapeutic agents and/or instructions,for example, instructions for using the kit. In one aspect, the kitcomprises one or more solid pharmaceutical dosage units (such as tabletsor capsules) comprising a solid state form of the present disclosure andinstructions for administering the one or more dosage forms to asubject.

In one embodiment, the kit comprises a first dosage unit and a seconddosage unit, wherein the first dosage unit is a solid pharmaceuticaldosage unit comprising a solid state form of the present disclosure, andthe second dosage unit comprises a second therapeutic agent. In oneaspect, the second therapeutic agent is one of the therapeutic agentsidentified in the previous discussion relating to combination therapies.In another aspect, the second therapeutic agent is an immunosuppressant.In another aspect, the second therapeutic agent is a therapeutic agentfor treating systemic lupus erythematosus. In another aspect, the secondtherapeutic agent is acetaminophen. In another aspect, the secondtherapeutic agent is methotrexate. In another aspect, the secondtherapeutic agent is a TNF antagonist, such as a humanized or humananti-TNF antibody (e.g., adalimumab, infliximab, golimumab, certolizumabpegol, tocilizumab, or etanercept).

X. METHODS OF PREPARATION

The present disclosure also relates to methods for preparing a solidstate form of Compound 1. In one aspect, the solid state form preparedis the Amorphous Freebase. In another aspect, the solid state formprepared is the Freebase Hydrate Form B. In another aspect, the solidstate form prepared is the Freebase Hydrate Form C. In another aspect,the solid state form prepared is the Tartrate Hydrate. In anotheraspect, the solid state form prepared is the Freebase Anhydrate Form D.

A. Preparation of Amorphous Freebase

The present disclosure relates to methods for preparing the AmorphousFreebase. In one embodiment, the method comprises dehydrating theFreebase Hydrate Form B to provide the Amorphous Freebase. In anotherembodiment, the method comprises desolvating the Freebase Solvate Form Ato provide the Amorphous Freebase. A wide range of process conditionscan be employed for the dehydration/desolvation. The dehydration can beconducted, for example, under ambient conditions or in a vacuum oven.FIG. 1A schematically illustrates one method of preparing the AmorphousFreebase by dehydration of the Freebase Hydrate Form B.

In another embodiment, the method comprises dissolving Compound 1 in asolvent or mixture of solvents; and adjusting the pH of the solvent ormixture of solvents to a pH greater than about 8 to initiateprecipitation of the Amorphous Freebase. In one aspect, the solvent ormixture of solvents comprises water. In another aspect, the pH isadjusted to a pH greater than about 9. In another aspect, the pH isadjusted to a pH greater than about 10. In another aspect, the pH isadjusted to a pH greater than about 11. In another aspect, the pH isadjusted to a pH of at least about 9.

In still other embodiments, the method comprises preparing the AmorphousFreebase using a method selected from the group consisting of impingingjet, spray drying, and hot-melt extrusion.

B. Preparation of Crystalline Freebase Solvate Form A and CrystallineFreebase Hydrate Form B

The present disclosure additionally relates to methods for preparing theFreebase Solvate Form A and Freebase Hydrate Form B. In one embodiment,the method comprises dissolving Compound 1 in a solvent or mixture ofsolvents comprising an anti-solvent; and maintaining the solvent ormixture of solvents at a temperature less than about 15° C. for anamount of time sufficient to initiate crystallization of the FreebaseSolvate Form A or the Freebase Hydrate Form B. The anti-solvent cancomprise, for example, water. The solvent or mixture of solvents cancomprise a polar solvent such as a solvent is selected from the groupconsisting of methanol, ethanol, n-butylamine, acetone, acetonitrile,ethyl formate, methyl acetate, ethyl acetate, methyl ethyl ketone,methyl isobutyl ketone, methyl isobutyl ketone, methyl tert-butyl ether,and isopropyl acetate. The Freebase Solvate Form A and Freebase HydrateForm B exhibit similar PXRD patterns, and are therefore isostructural.The method generally is conducted at sub-ambient temperatures, forexample, less than about 10° C., less than about 5° C., or less thanabout 0° C. In certain aspects, the process further comprises seedingthe solvent or mixture of solvents with crystals of the Freebase SolvateForm A or the Freebase Hydrate Form B.

C. Preparation of Crystalline Freebase Hydrate Form C

The present disclosure additionally relates to methods for preparing theFreebase Hydrate Form C. In one embodiment, the method comprisesdissolving Compound 1 in a solvent or mixture of solvents; andinitiating crystallization to provide the Freebase Hydrate Form C. Thesolvent or mixture of solvents generally will comprise an anti-solvent(such as water) which can be present in the solvent or mixture ofsolvents before, or added to the solvent or mixture of solvents after,the Compound 1 is dissolved in the solvent or mixture of solvents. Thesolvent or mixture of solvents can comprise, for example, one or morepolar solvents (such as polar solvent selected from the group consistingof ethanol and ethyl acetate); one or more nonpolar solvents (such as anonpolar solvent is selected from the group consisting of hexane andheptane); or at least one polar solvent and at least one nonpolarsolvent. In one aspect, the solvent or mixture of solvents is a ternarysolvent mixture comprising ethyl acetate, heptane, and water. The methodgenerally is conducted at temperatures less than about 30° C., less thanabout 20° C., or less than about 10° C. In certain aspects, theinitiating crystallization step comprises mixing the solvent or mixtureof solvents to provide sufficient agitation to initiate crystallization.In certain aspects, the initiating crystallization step comprisesseeding the solvent or mixture of solvents with crystals of the FreebaseHydrate Form C. In certain aspects, the initiating crystallization stepcomprises both mixing the solvent or mixture of solvents and seeding thesolvent or mixture of solvents with crystals of the Freebase HydrateForm C.

In one embodiment, Compound 1 is first prepared according to any of themethods set forth herein, a reaction mixture comprising Compound 1 isfiltered, and the resulting solution is suspended in a solvent ormixture of solvents. The solvent or mixture of solvents can comprise,for example, one or more polar solvents (such as polar solvent selectedfrom the group consisting of ethanol and ethyl acetate); one or morenonpolar solvents (such as a nonpolar solvent is selected from the groupconsisting of hexane and heptane); or at least one polar solvent and atleast one nonpolar solvent. In one particular embodiment, the solvent isethyl acetate, or a mixture of ethyl acetate and water. In certainaspects, the initiating crystallization step comprises seeding thesolvent or mixture of solvents with crystals of the Freebase HydrateForm C. In one particular aspect, the crystallization occurs in a wetmill.

FIG. 1B schematically illustrates one method of preparing the FreebaseHydrate Form C.

D. Preparation of Crystalline Freebase Anhydrate Form D

The present disclosure additionally relates to methods for preparing theFreebase Anhydrate Form D. In one embodiment, the method comprisesdissolving Compound 1 in a solvent or mixture of solvents; andinitiating crystallization to provide the Freebase Anhydrate Form D. Thesolvent or mixture of solvents will be water-free, or close towater-free. In embodiments, the solvent or mixture of solvents will havea water content of less than about 0.15 wt %, or less than about 0.10wt. %, or less than about 0.05 wt. %, or about 0 wt. % at 23° C. In oneembodiment, the solvent or mixture of solvents will have a wateractivity of about 2.4% or less, or about 2.2% or less, or about 2.0% orless, or about 1.5% or less. The solvent or mixture of solvents cancomprise, for example, ethyl acetate (EtOAc), heptane, and combinationsthereof. In one embodiment, the solvent system comprises a mixture ofheptane in ethyl acetate. In some embodiments, the solvent systemcomprises about 10 wt. %, or about 20 wt. %, or about 30 wt. %, or about40 wt. % heptane in ethyl acetate. The method generally is conducted attemperatures of at least about 7° C., at least about 23° C., at leastabout 25° C. or less, or at least about 30° C. In one embodiment, themethod is conducted at about 23° C. In certain aspects, the initiatingcrystallization step comprises mixing the solvent or mixture of solventsto provide sufficient agitation to initiate crystallization. In certainaspects, the initiating crystallization step comprises seeding thesolvent or mixture of solvents with crystals of the Freebase AnhydrateForm D. In certain aspects, the initiating crystallization stepcomprises both mixing the solvent or mixture of solvents and seeding thesolvent or mixture of solvents with crystals of the Freebase AnhydrateForm D.

E. Preparation of Crystalline Tartrate Hydrate

The present disclosure additionally relates to methods for preparing theTartrate Hydrate. In one embodiment, the method comprises dissolvingCompound 1 and L-tartaric acid in a solvent or mixture of solvents toform a crystallization solution; and crystallizing the Tartrate Hydratefrom the crystallization solution. The solvent or mixture of solventscan comprise, for example, water and/or, for example, one or more polarsolvents (such as isopropyl acetate). The solvent or mixture of solventsalso can comprise an anti-solvent (such as isopropyl acetate). Incertain aspects, the process further comprises seeding the solvent ormixture of solvents with crystals of the Tartrate Hydrate.

The crystallization generally is conducted at a temperature less thanabout 40° C. When an anti-solvent is used, a moderate rate of additionis employed for the anti-solvent as a faster rate of addition typicallyresults in the precipitation of an amorphous tartrate and a slower rateof addition allows the resulting slurry to thicken. Proper control offiltration, washing, and drying may be needed to avoid potential issuesassociated with consolidation of the filter cake, including solvententrapment, solid properties (e.g., hard, chunky solids) and handing,and damage to equipment. Depending upon the properties of the driedTartrate Hydrate material, milling may require a mechanical impact-typeof mills rather than a shear-based mill (such as a co-mill).

FIG. 1C schematically illustrates one method of preparing the TartrateHydrate.

XI. PRODUCT-BY-PROCESS

The present disclosure also relates to a solid state form of Compound 1prepared in accordance with any of the methods described in thedisclosure.

In one embodiment, the solid state form prepared is the AmorphousFreebase.

In one embodiment, the solid state form prepared is the Freebase HydrateForm B.

In one embodiment, the solid state form prepared is the Freebase HydrateForm C.

In one embodiment, the solid state form prepared is the TartrateHydrate.

In one embodiment, the solid state form prepared is Freebase AnhydrateForm D.

XII. ADDITIONAL EMBODIMENTS

In some aspects, the disclosure is directed to the following additionalembodiments:

Embodiment A

A crystalline hydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment A1

The crystalline hydrate of Embodiment A, wherein the hydrate is ahemihydrate.

Embodiment A2

The crystalline hydrate of Embodiment A or Embodiment A1 having an X-raypowder diffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2,and 21.7±0.2 degrees two theta when measured at about 25° C. withmonochromatic Kα1 radiation.

Embodiment A3

The crystalline hydrate of Embodiment A2, wherein the X-ray powderdiffraction pattern is further characterized by a peak at 15.5±0.2degrees two theta when measured at about 25° C. with monochromatic Kα1radiation.

Embodiment A4

The crystalline hydrate of Embodiment A3, wherein the X-ray powderdiffraction pattern is further characterized by a peak at 17.0±0.2degrees two theta when measured at about 25° C. with monochromatic Kα1radiation.

Embodiment A5

The crystalline hydrate of Embodiment A4, wherein the X-ray powderdiffraction pattern is further characterized by a peak at 20.9±0.2degrees two theta when measured at about 25° C. with monochromatic Kα1radiation.

Embodiment A6

The crystalline hydrate of any one of Embodiments A to A5, wherein thecrystalline hydrate has an X-ray powder diffraction patternsubstantially as shown in FIG. 3C.

Embodiment A7

The crystalline hydrate of any one of Embodiments A to A6, wherein thecrystalline hydrate has a thermogravimetric analysis profilesubstantially as shown in FIG. 4E.

Embodiment A8

The crystalline hydrate of any one of Embodiments A to A7, wherein thecrystalline hydrate has a differential scanning calorimetry profilesubstantially as shown in FIG. 5C.

Embodiment A9

The crystalline hydrate of any one of Embodiments A to A8, wherein thecrystalline hydrate has a moisture sorption isotherm profilesubstantially as shown in FIG. 6B.

Embodiment A10

The crystalline hydrate of any one of Embodiments A to A9, wherein thecrystalline hydrate has a thermogravimetric analysis profile showing aweight loss of about 2.3% to about 2.6% between about 120° C. and 160°C. when heated at a rate of 10° C./minute; and a differential scanningcalorimetry profile comprising an endotherm between about 120° C. andabout 170° C. when heated at a rate of 10° C./minute.

Embodiment A11

The crystalline hydrate of any one of Embodiments A to A10, wherein thecrystalline hydrate has an orthorhombic lattice type.

Embodiment A12

The crystalline hydrate of Embodiment A11, wherein the crystallinehydrate has a P2₁2₁2₁ space group.

Embodiment A13

The crystalline hydrate of Embodiment A11 or A12, wherein thecrystalline hydrate has unit cell a, b and c values of about 12.7 Å,about 13.1 Å, and about 22.6 Å, respectively

Embodiment A14

The crystalline hydrate of Embodiment A having an X-ray powderdiffraction pattern characterized by peaks at 3.1±0.2, 9.3±0.2, and12.0±0.2 degrees two theta when measured at about 25° C. withmonochromatic Kα1 radiation.

Embodiment A15

The crystalline hydrate of Embodiment A14, wherein the X-ray powderdiffraction pattern is further characterized by a peak at 20.8±0.2degrees two theta when measured at about 25° C. with monochromatic Kα1radiation.

Embodiment A16

The crystalline hydrate of Embodiment A15, wherein the X-ray powderdiffraction pattern is further characterized by a peak at 25.0±0.2degrees two theta when measured at about 25° C. with monochromatic Kα1radiation.

Embodiment A17

The crystalline hydrate of any one of Embodiments A or A14 to A16,wherein the crystalline hydrate has an X-ray powder diffraction patternsubstantially as shown in FIG. 3B.

Embodiment A18

The crystalline hydrate of any one of Embodiments A or A14 to A17,wherein the crystalline hydrate has a thermogravimetric analysis profilesubstantially as shown in FIG. 4D.

Embodiment A19

The crystalline hydrate of any one of Embodiments A or A14 to A18,wherein the crystalline hydrate has a differential scanning calorimetryprofile substantially as shown in FIG. 5B.

Embodiment A20

A pharmaceutical composition comprising a crystalline hydrate of any oneof Embodiments A to A19, and a pharmaceutically acceptable carrier.

Embodiment A21

The pharmaceutical composition of Embodiment A20, wherein greater thanabout 90% by weight of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamidein the composition is a crystalline hydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)-pyrrolidine-1-carboxamidehaving an X-ray powder diffraction pattern characterized by peaks at13.4±0.2, 15.1±0.2, and 21.7±0.2 degrees two theta when measured atabout 25° C. with monochromatic Kα1 radiation.

Embodiment A22

The pharmaceutical composition of Embodiment A20, wherein greater thanabout 90% by weight of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamidein the composition is a crystalline hydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)-pyrrolidine-1-carboxamidehaving an X-ray powder diffraction pattern comprising peaks at 3.1±0.2,9.3±0.2, and 12.0±0.2 degrees two theta when measured at about 25° C.with monochromatic Kα1 radiation.

Embodiment B

Amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment B1

The amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof Embodiment B comprising less than about 12% by weight water.

Embodiment B2

The amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof Embodiment B or B1 having a glass transition temperature onset atabout 119° C.

Embodiment B3

The amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any of Embodiments B to B2 having a glass transition temperaturemidpoint at about 122° C.

Embodiment B4

A pharmaceutical composition comprising the amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments B to B3, and a pharmaceutically acceptablecarrier.

Embodiment B5

The pharmaceutical composition of Embodiment B4, wherein greater thanabout 90% by weight of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamidein the composition is amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment C

A crystalline anhydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment C1

The crystalline anhydrate of Embodiment C having an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta when measured atabout 25° C. with monochromatic Kα1 radiation.

Embodiment C2

The crystalline anhydrate of Embodiment C1, wherein the X-ray powderdiffraction pattern is further characterized by a peak at 4.0±0.2degrees two theta when measured at about 25° C. with monochromatic Kα1radiation.

Embodiment C3

The crystalline anhydrate of Embodiment C2, wherein the X-ray powderdiffraction pattern is further characterized by a peak at 19.0±0.2degrees two theta when measured at about 25° C. with monochromatic Kα1radiation.

Embodiment C4

The crystalline anhydrate of Embodiment C3, wherein the X-ray powderdiffraction pattern is further characterized by peaks at 18.4±0.2,23.0±0.2, and 24.7±0.2 degrees two theta when measured at about 25° C.with monochromatic Kα1 radiation.

Embodiment C5

The crystalline anhydrate of any one of Embodiments C to C4, wherein thecrystalline anhydrate has an X-ray powder diffraction patternsubstantially as shown in FIG. 3J.

Embodiment C6

The crystalline anhydrate of any one of Embodiments C to C5, wherein thecrystalline anhydrate has a thermogravimetric analysis profilesubstantially as shown in FIG. 4I.

Embodiment C7

The crystalline anhydrate of any one of Embodiments C to C6, wherein thecrystalline anhydrate has a differential scanning calorimetry profilesubstantially as shown in FIG. 5E.

Embodiment C8

The crystalline anhydrate of any one of Embodiments C to C7, wherein thecrystalline anhydrate has a moisture sorption isotherm profilesubstantially as shown in FIG. 6D.

Embodiment C9

The crystalline anhydrate of any one of Embodiments C to C8, wherein thecrystalline anhydrate has an orthorhombic lattice type.

Embodiment C10

The crystalline anhydrate of any one of Embodiments C to C9, wherein thecrystalline anhydrate has a P2₁2₁2 space group.

Embodiment C11

The crystalline anhydrate of any one of Embodiments C to C10, whereinthe crystalline anhydrate has unit cell a, b and c values of about 43.8Å, about 8.6 Å, and about 9.2 Å, respectively.

Embodiment C12

The crystalline anhydrate of any one of Embodiments C to C11, whereinthe crystalline anhydrate has a thermogravimetric analysis profileshowing a weight loss of about 0.5% to about 0.8% between about 43° C.and 188° C. when heated at a rate of 10° C./minute; and a differentialscanning calorimetry profile comprising an endotherm between about 180°C. and about 220° C. when heated at a rate of 10° C./minute.

Embodiment C13

The crystalline anhydrate of any one of Embodiments C to C12, whereinthe crystalline anhydrate has an onset melting point of about 199.6° C.

Embodiment C14

A pharmaceutical composition comprising a crystalline anhydrate of anyone of claims C to C13, and a pharmaceutically acceptable carrier.

Embodiment C15

The pharmaceutical composition of Embodiment C14, wherein greater thanabout 90% by weight of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamidein the composition is a crystalline anhydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)-pyrrolidine-1-carboxamidehaving an X-ray powder diffraction pattern characterized by peaks at8.0±0.2, 9.7±0.2, 14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two thetawhen measured at about 25° C. with monochromatic Kα1 radiation.

Embodiment D

A pharmaceutical composition comprising(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamidetartrate, from about 10 w/w % to about 35 w/w % of an organic acidselected from the group consisting of tartaric acid, fumaric acid,citric acid, succinic acid, malic acid, and combinations thereof, and apharmaceutically acceptable carrier.

Embodiment D1

The pharmaceutical composition of Embodiment D, wherein the tartrate iscrystalline(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamidetartrate tetrahydrate.

Embodiment D2

The pharmaceutical composition of Embodiment D or Embodiment D1, whereinthe tartrate has an X-ray powder diffraction pattern characterized bypeaks at 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees two theta when measuredat about 25° C. with monochromatic Kα1 radiation.

Embodiment D3

The pharmaceutical composition of any one of Embodiments D to D2,wherein the tartrate has an X-ray powder diffraction patternsubstantially as shown in FIG. 3D.

Embodiment D4

The pharmaceutical composition of any one of Embodiments D to D3,wherein the tartrate has a thermogravimetric analysis profilesubstantially as shown in FIG. 4F.

Embodiment D5

The pharmaceutical composition of any one of Embodiments D to D4,wherein the tartrate has a differential scanning calorimetry profilesubstantially as shown in FIG. 5D.

Embodiment D6

The pharmaceutical composition of any one of Embodiments D to D5,wherein the tartrate has a moisture sorption isotherm profilesubstantially as shown in FIG. 6C.

Embodiment D7

The pharmaceutical composition of any one of Embodiments D to D6,wherein greater than about 90% by weight of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamidein the composition is crystalline(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamidetartrate tetrahydrate.

Embodiment E

The pharmaceutical composition of any one of Embodiments A20 to A22, B4,B5, C14, C15, or D to D7, wherein the composition comprises a releasecontrol polymer.

Embodiment E1

The pharmaceutical composition of Embodiment E, wherein the releasecontrol polymer is a hydrophilic polymer.

Embodiment E2

The pharmaceutical composition of Embodiment E or E1, wherein therelease control polymer is a cellulose derivative with a viscositybetween 1000 and 150,000 mPa-s.

Embodiment E3

The pharmaceutical composition of any one of Embodiments E to E2,wherein the release control polymer is selected from the groupconsisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose, andcopolymers of acrylic acid crosslinked with a polyalkenyl polyether, andcombinations thereof.

Embodiment E4

The pharmaceutical composition of any one of Embodiments E to E3,wherein the release control polymer is selected from the groupconsisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose, andcombinations thereof.

Embodiment E5

The pharmaceutical composition of any one of Embodiments E to E4,wherein the release control polymer is hydroxypropylmethyl cellulose.

Embodiment E6

The pharmaceutical composition of Embodiment E5, wherein thehydroxypropylmethyl cellulose is grade E, F, or K.

Embodiment E6

The pharmaceutical composition of Embodiment E5, wherein thehydroxypropylmethyl cellulose is Hypromellose 2208.

Embodiment E7

The pharmaceutical composition of any one of Embodiments E to E6,wherein the composition comprises a filler.

Embodiment E8

The pharmaceutical composition of Embodiment E7, wherein the filler isselected from the group consisting of microcrystalline cellulose,mannitol, and combinations thereof.

Embodiment E9

The pharmaceutical composition of any one of Embodiments E to E8,wherein the composition comprises a lubricant.

Embodiment E10

The pharmaceutical composition of any one of Embodiments E to E9,wherein the composition comprises a glidant.

Embodiment E11

The pharmaceutical composition of any one of Embodiments E to E10,wherein the composition comprises a pH modifier.

Embodiment E12

The pharmaceutical composition of Embodiment E11, wherein the pHmodifier is selected from the group consisting of tartaric acid, fumaricacid, citric acid, succinic acid, malic acid, and combinations thereof.

Embodiment I3

The pharmaceutical composition of Embodiments E11 or E12, wherein the pHmodifier is selected from the group consisting of tartaric acid, fumaricacid, citric acid, succinic acid, and combinations thereof.

Embodiment E14

The pharmaceutical composition of any one of Embodiments E11 to E13,wherein the pH modifier is selected from the group consisting oftartaric acid, fumaric acid, and combinations thereof.

Embodiment E15

The pharmaceutical composition of any one of Embodiments E11 to E14,wherein the pH modifier is tartaric acid.

Embodiment E16

The pharmaceutical composition of any one of Embodiments E1 to E14,wherein the pH modifier is fumaric acid or citric acid.

Embodiment E17

The pharmaceutical composition of any one of Embodiments E11 to E16,wherein the pH modifier is present in an amount from about 10 to about35 w/w %.

Embodiment E18

The pharmaceutical composition of any one of Embodiments E11 to E17,wherein the pH modifier is present in an amount from about 20 to about35 w/w %.

Embodiment E19

The pharmaceutical composition of any one of Embodiments E11 to E18,wherein the pH modifier is present in an amount from about 20 to about30 w/w %.

Embodiment E20

The pharmaceutical composition of any one of Embodiments E11 to E19,wherein the pH modifier is present in an amount from about 20 to about25 w/w %.

Embodiment E21

The pharmaceutical composition of any one of Embodiments E11 to E20,wherein the pH modifier is present in an amount of about 10 w/w %.

Embodiment E22

The pharmaceutical composition of any one of Embodiments E11 to E20,wherein the pH modifier is present in an amount of about 20 w/w %.

Embodiment E23

The pharmaceutical composition of any one of Embodiments E11 to E20,wherein the pH modifier is present in an amount of about 30 w/w %.

Embodiment F

A method of treating a JAK-1 associated condition, the method comprisingadministering a therapeutically effective amount of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 to a subjectsuffering from or susceptible to the condition.

Embodiment F1

The method of embodiment F, wherein the therapeutically effective amountof the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideis selected from the group consisting of 7.5 mg once daily, 15 mg oncedaily, 30 mg once daily, and 45 mg once daily.

Embodiment F2

A method of treating a JAK-1 associated condition, the method comprisingadministering the pharmaceutical composition of any one of EmbodimentsA20 to A22, B4, B5, C14, C15, D to D7, or E to E23 to a subjectsuffering from or susceptible to the condition.

Embodiment F2a

The method of any one of Embodiments F to F2, wherein the condition isselected from the group consisting of immunomodulation, inflammation,and proliferative disorders.

Embodiment F2b

The method of any one of Embodiments F to F2a, wherein the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideis the Freebase Hydrate Form C.

Embodiment F3

A(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 for use intreating a JAK-1 associated condition. In certain aspects of EmbodimentE3, the use comprising administering a therapeutically effective amountof the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 to a subjectsuffering from or susceptible to the condition. In one embodiment, thecondition is selected from the group consisting of immunomodulation,inflammation, and proliferative disorders. In certain aspects, inEmbodiment F3, the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamidemay be the Freebase Hydrate Form C. In some aspects, in Embodiment F3,the therapeutically effective amount of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideis selected from the group consisting of 7.5 mg once daily, 15 mg oncedaily, 30 mg once daily, and 45 mg once daily.

Embodiment F4

A pharmaceutical composition of any one of Embodiments A20 to A22, B4,B5, C14, C15, D to D7, or E to E23 for use in treating a JAK-1associated condition. In certain aspects of Embodiment F4, the usecomprises administering the pharmaceutical composition to a subjectsuffering from or susceptible to the condition. In one embodiment, thecondition is selected from the group consisting of immunomodulation,inflammation, and proliferative disorders. In certain aspects, inEmbodiment F4, the composition comprises the Freebase Hydrate Form C.

Embodiment G

A method of treating a condition selected from the group consisting ofrheumatoid arthritis, juvenile idiopathic arthritis, Crohn's disease,ulcerative colitis, psoriasis, plaque psoriasis, nail psoriasis,psoriatic arthritis, ankylosing spondylitis, alopecia areata,hidradenitis suppurativa, atopic dermatitis, and systemic lupuserythematosus, the method comprising administering a therapeuticallyeffective amount of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 to a subjectsuffering from or susceptible to the condition.

Embodiment G1

The method of embodiment G, wherein the therapeutically effective amountof the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideis selected from the group consisting of 7.5 mg once daily, 15 mg oncedaily, 30 mg once daily, and 45 mg once daily.

Embodiment G2

A method of treating a condition selected from the group consisting ofrheumatoid arthritis, juvenile idiopathic arthritis, Crohn's disease,ulcerative colitis, psoriasis, plaque psoriasis, nail psoriasis,psoriatic arthritis, ankylosing spondylitis, alopecia areata,hidradenitis suppurativa, atopic dermatitis, and systemic lupuserythematosus, the method comprising administering the pharmaceuticalcomposition of any one of Embodiments A20 to A22, B4, B5, C14, C15, D toD7, or E to E23 to a subject suffering from or susceptible to thecondition.

Embodiment G3

The method of any one of Embodiments G to G2, wherein the condition isrheumatoid arthritis.

Embodiment G3a

The method of any one of Embodiments G to G3, wherein the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideis the Freebase Hydrate Form C.

Embodiment G4

A(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 for use intreating a condition selected from the group consisting of rheumatoidarthritis, juvenile idiopathic arthritis, Crohn's disease, ulcerativecolitis, psoriasis, plaque psoriasis, nail psoriasis, psoriaticarthritis, ankylosing spondylitis, alopecia areata, hidradenitissuppurativa, atopic dermatitis, and systemic lupus erythematosus. Incertain aspects of Embodiment G4, the use comprises administering atherapeutically effective amount of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 to a subjectsuffering from or susceptible to the condition. In one embodiment, thecondition is rheumatoid arthritis. In some instances, in Embodiment G4,the therapeutically effective amount of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamidemay be selected from the group consisting of 7.5 mg once daily, 15 mgonce daily, 30 mg once daily, and 45 mg once daily. In certain aspects,in Embodiment G4, the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamidemay be the Freebase Hydrate Form C.

Embodiment G5

A pharmaceutical composition of any one of Embodiments A20 to A22, B4,B5, C14, C15, D to D7, or E to E23 for use in treating a conditionselected from the group consisting of rheumatoid arthritis, juvenileidiopathic arthritis, Crohn's disease, ulcerative colitis, psoriasis,plaque psoriasis, nail psoriasis, psoriatic arthritis, ankylosingspondylitis, alopecia areata, hidradenitis suppurativa, atopicdermatitis, and systemic lupus erythematosus. In certain aspects ofEmbodiment G5, the use comprises administering the pharmaceuticalcomposition to a subject suffering from or susceptible to the condition.In one embodiment, the condition is rheumatoid arthritis. In certainaspects, in Embodiment G5, the composition comprises Freebase HydrateForm C.

Embodiment H

A method of treating moderate to severe active rheumatoid arthritis, themethod comprising administering a therapeutically effective amount ofthe(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 to a subjectsuffering from or susceptible to the condition.

Embodiment H1

The method of Embodiment H wherein the therapeutically effective amountof the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideis about 7.5 mg once daily.

Embodiment H2

The method of Embodiment H wherein the therapeutically effective amountof the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideis about 15 mg once daily.

Embodiment H3

The method of Embodiment H wherein the therapeutically effective amountof the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideis about 30 mg once daily.

Embodiment H4

The method of Embodiment H wherein the therapeutically effective amountof the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideis about 45 mg once daily.

Embodiment H5

A method of treating moderate to severe active rheumatoid arthritis, themethod comprising administering the pharmaceutical composition of anyone of Embodiments A20 to A22, B4, B5, C14, C15, D to D7, or E to E23 toa subject suffering from or susceptible to the condition.

Embodiment H6

The method of any one of Embodiments H to H5, wherein the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideis the Freebase Hydrate Form C.

Embodiment H7

The method of any one of Embodiments H to H6, wherein the subject hashad an inadequate response to methotrexate.

Embodiment H8

The method of any one of Embodiments H to H7, wherein the subject hashad an inadequate response to biologics medicines approved forrheumatoid arthritis.

Embodiment H9

The method of any one of Embodiments H to H8, wherein the subject hasnot previously been administered biologics medicines approved forrheumatoid arthritis.

Embodiment H10

A(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 for use intreating moderate to severe active rheumatoid arthritis. In certainaspects of Embodiment H10, the use comprises administering atherapeutically effective amount of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19,13 to B3, or C to C13 to a subjectsuffering from or susceptible to the condition. In one aspect, inEmbodiment H10, the therapeutically effective amount of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideis about 7.5 mg or about 15 mg or about 30 mg or about 45 mg once daily.

Embodiment H11

A pharmaceutical composition of any one of Embodiments A20 to A22, B4,B. C14, C15, D to D7, or E to E23 for use in treating moderate to severeactive rheumatoid arthritis. In certain aspects of Embodiment H11, theuse comprises administering the pharmaceutical composition to a subjectsuffering from or susceptible to the condition.

Embodiment I

A method of treating a subject having rheumatoid arthritis, the methodcomprising administering to the subject about 7.5 mg, per unit dosageform of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideorally once daily.

Embodiment I1

A method of treating a subject having rheumatoid arthritis, the methodcomprising administering to the subject about 7.5 mg, per unit dosageform of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 orally oncedaily.

Embodiment I1a

A(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 for use intreating a subject having rheumatoid arthritis. In certain aspects ofEmbodiment E1a, the use comprises administering to the subject about 7.5mg, per unit dosage form of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 orally oncedaily.

Embodiment I2

A method of treating a subject having rheumatoid arthritis, the methodcomprising administering to the subject orally once daily thepharmaceutical composition of any one of Embodiments A20 to A22, B4, B5,C14, C15, D to D7, or E to E23, wherein the composition comprises about7.5 mg, per unit dosage form of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment I3

A pharmaceutical composition of any one of Embodiments A20 to A22, B4,B5, C14, C15, D to D7, or E to E23 for use in treating a subject havingrheumatoid arthritis. In certain aspects of Embodiment I3, the usecomprises administering to the subject orally once daily thepharmaceutical composition, wherein the composition comprises about 7.5mg, per unit dosage form of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment I4

A method of treating a subject having rheumatoid arthritis, the methodcomprising administering to the subject about 15 mg, per unit dosageform of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideorally once daily.

Embodiment I5

A method of treating a subject having rheumatoid arthritis, the methodcomprising administering to the subject about 15 mg, per unit dosageform of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 orally oncedaily.

Embodiment I6

A(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 for use intreating a subject having rheumatoid arthritis. In certain aspects ofEmbodiment I6, the use comprises administering to the subject about 15mg, per unit dosage form of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 orally oncedaily.

Embodiment I7

A method of treating a subject having rheumatoid arthritis, the methodcomprising administering to the subject orally once daily thepharmaceutical composition of any one of Embodiments A20 to A22, B4, B5,C14, C15, D to D7, or E to E23, wherein the composition comprises about15 mg, per unit dosage form of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment I8

A pharmaceutical composition of any one of Embodiments A20 to A22, B4,B5, C14, C15, D to D7, or E to E23 for use in treating a subject havingrheumatoid arthritis. In certain aspects of Embodiment I8, the usecomprises administering to the subject orally once daily thepharmaceutical composition, wherein the composition comprises about 15mg, per unit dosage form of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment I9

A method of treating a subject having rheumatoid arthritis, the methodcomprising administering to the subject about 30 mg, per unit dosageform of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideorally once daily.

Embodiment I10

A method of treating a subject having rheumatoid arthritis, the methodcomprising administering to the subject about 30 mg, per unit dosageform of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 orally oncedaily.

Embodiment I11

A(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 for use intreating a subject having rheumatoid arthritis. In certain aspects ofEmbodiment I11, the use comprises administering to the subject about 30mg, per unit dosage form of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 orally oncedaily.

Embodiment I12

A method of treating a subject having rheumatoid arthritis, the methodcomprising administering to the subject orally once daily thepharmaceutical composition of any one of Embodiments A20 to A22, B4, B5,C14, C15, D to D7, or E to E23, wherein the composition comprises about30 mg, per unit dosage form of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment I13

A pharmaceutical composition of any one of Embodiments A20 to A22, B4,B5, C14, C15, D to D7, or E to E23 for use in treating a subject havingrheumatoid arthritis. In certain aspects of Embodiment I13, the usecomprises administering to the subject orally once daily thepharmaceutical composition, wherein the composition comprises about 30mg, per unit dosage form of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment I14

A method of treating a subject having rheumatoid arthritis, the methodcomprising administering to the subject about 45 mg, per unit dosageform of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideorally once daily.

Embodiment I15

A method of treating a subject having rheumatoid arthritis, the methodcomprising administering to the subject about 45 mg, per unit dosageform of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 orally oncedaily.

Embodiment I16

A(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19. B to B3, or C to C13 for use intreating a subject having rheumatoid arthritis. In certain aspects ofEmbodiment I16, the use comprises administering to the subject about 45mg, per unit dosage form of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof any one of Embodiments A to A19, B to B3, or C to C13 orally oncedaily.

Embodiment I17

A method of treating a subject having rheumatoid arthritis, the methodcomprising administering to the subject orally once daily thepharmaceutical composition of any one of Embodiments A20 to A22, B4, B5,C14, C15, D to D7, or E to E23, wherein the composition comprises about45 mg, per unit dosage form of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment I18

A pharmaceutical composition of any one of Embodiments A20 to A22, B4,B5, C14, C15, D to D7, or E to E23 for use in treating a subject havingrheumatoid arthritis. In certain aspects of Embodiment I18, the usecomprises administering to the subject orally once daily thepharmaceutical composition, wherein the composition comprises about 45mg, per unit dosage form of the(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment J

A method for the preparation of the crystalline hydrate of Embodiment A1or A2, the method comprising:

dissolving(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamidein a solvent or mixture of solvents; and

initiating crystallization to provide the crystalline hydrate.

Embodiment J1

The method of Embodiment J, wherein the solvent or mixture of solventscomprises an anti-solvent.

Embodiment J2

The method of Embodiment J or J1, wherein the solvent or mixture ofsolvents comprises a polar solvent.

Embodiment J3

The method of Embodiment J or J1, wherein the solvent or mixture ofsolvents comprises a nonpolar solvent.

Embodiment J4

The method of any one of Embodiments J to J3, wherein the initiatingcrystallization step comprises mixing the solvent or mixture ofsolvents.

Embodiment J5

The method of any one of Embodiments J to J4, wherein the initiatingcrystallization step comprises seeding the solvent or mixture ofsolvents with crystals of the crystalline hydrate of Embodiment A1 orA2.

Embodiment J6

The method of any one of Embodiments J to J5, wherein the initiatingcrystallization step comprises both mixing the solvent or mixture ofsolvents and seeding the solvent or mixture of solvents with crystals ofthe crystalline hydrate of Embodiment A1 or A2.

Embodiment J7

The method of Embodiment J, wherein the method comprises adding ananti-solvent to the solvent or mixture of solvents, and the solvent ormixture of solvents comprises a polar solvent.

Embodiment J8

The method of Embodiments J, wherein the method comprises adding ananti-solvent to the solvent or mixture of solvents, and the solvent ormixture of solvents comprises a nonpolar solvent.

Embodiment J9

The method of any one of Embodiments J, J7, or J8, wherein the methodcomprises adding an anti-solvent to the solvent or mixture of solvents,and seeding the solvent or mixture of solvents with crystals of thecrystalline hydrate of Embodiment A1 or A2.

Embodiment J10

The method of any one of Embodiments J, J7, or J8, wherein the methodcomprises adding an anti-solvent to the solvent or mixture of solvents,and mixing the solvent or mixture of solvents.

Embodiment J11

The method of any one of Embodiments J, J7, or J8, wherein the methodcomprises adding an anti-solvent to the solvent or mixture of solvents,and both seeding the solvent or mixture of solvents with crystals of thecrystalline hydrate of claim 2 and mixing the solvent or mixture ofsolvents.

Embodiment J12

The method of any one of Embodiments J to J11, wherein thecrystallization occurs in a wet mill.

Embodiment K

A method for the preparation of the crystalline hydrate of EmbodimentA14, the method comprising:

dissolving(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamidein a solvent or mixture of solvents comprising an anti-solvent; and

maintaining the solvent or mixture of solvents at a temperature lessthan about 15° C. for an amount of time sufficient to initiatecrystallization of the crystalline hydrate.

Embodiment K1

The method of Embodiment K, wherein the solvent or mixture of solventscomprises a polar solvent.

Embodiment K2

The method of Embodiment K or K11, wherein the temperature is less thanabout 10° C.

Embodiment K3

The method of any one of Embodiments K to K2, wherein the processfurther comprises seeding the solvent or mixture of solvents withcrystals of the crystalline hydrate of Embodiment A14.

Embodiment L

A method for the preparation of the amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof Embodiment B, the method comprising dehydrating the crystallinehydrate of Embodiment A14 to provide the amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment L1

A method for the preparation of the amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideof Embodiment B, the method comprising:

dissolving(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamidein a solvent or mixture of solvents; and

adjusting the pH of the solvent or mixture of solvents to a pH greaterthan about 8 to initiate precipitation of the amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment L2

The method of Embodiment L1, wherein the solvent or mixture of solventscomprises water.

Embodiment L3

The method of Embodiment L1 or L2, wherein the pH of the solvent ormixture of solvents is adjusting to a pH equal to or greater than about12.

Embodiment M

A method for the preparation of the crystalline anhydrate of EmbodimentC, the method comprising:

dissolving(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamidein a solvent or mixture of solvents, wherein the solvent or mixture ofsolvents comprises less than about 0.15 wt. % of water; and

initiating crystallization to provide the crystalline anhydrate.

Embodiment M1

The method of Embodiment M, wherein the solvent or mixture of solventshas a water activity of about 2.4% or less.

Embodiment M2

The method of Embodiment M or M1, wherein the initiating crystallizationstep comprises mixing the solvent or mixture of solvents.

Embodiment M3

The method of Embodiment M2, wherein the mixing occurs at a temperatureof at least 23° C.

Embodiment M4

The method of any one of Embodiments M to M3, wherein the initiatingcrystallization step comprises seeding the solvent or mixture ofsolvents with crystals of the crystalline anhydrate of Embodiment C orC1.

Embodiment N

A crystalline hydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideprepared by the process of any of Embodiments J to J12.

Embodiment N1

A crystalline hydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideprepared by the process of any one of Embodiments K to K3.

Embodiment N2

Amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideprepared by the process of any one of Embodiments L to L3.

Embodiment N3

A crystalline anhydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideprepared by the process of any one of Embodiments M to M4.

Embodiment O

A process for preparing(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,or a pharmaceutically acceptable salt thereof, the process comprising:

a) reacting a compound of formula (I)

or a pharmaceutically acceptable salt thereof with trimethylsulfoxoniumchloride to form a compound of formula (II)

wherein PG is a protecting group;

-   -   b) contacting the compound of formula (II) with LiX and a        sulfonic acid to form a compound of formula (III)

wherein X is Br or Cl

-   -   c) reacting the compound of formula (III) with a compound of        formula (IV)

to produce a compound of formula (V)

-   -   wherein R₁ is selected from the group consisting of alkyl, aryl,        and —OR₂; R₂ is alkyl; and Ts is tosyl;    -   d) contacting the compound of formula (V) with a perfluoro acid        anhydride and an organic base to form a compound of formula (VI)

-   -   e) deprotecting the compound of formula (VI) and forming a        pharmaceutically acceptable salt of the compound of formula        (VII):

and

-   -   f) reacting the pharmaceutically acceptable salt of the compound        of formula (VII) with 2,2,2-trifluoroethylamine to produce        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment O1

The process of Embodiment O, wherein the pharmaceutically acceptablesalt of the compound of formula (I) is selected from the groupconsisting of a compound of formula (Ia) and a compound of formula (Ib)

wherein Cbz is carboxybenzyl.

Embodiment O2

The process of Embodiment O1, further comprising contacting the compoundof formula (Ia) or (Ib) with an acid prior to reacting totrimethylsulfoxonium chloride.

Embodiment O3

The process of Embodiment O2, wherein the acid is selected from thegroup consisting of a mineral acid or an organic acid.

Embodiment O4

The process of Embodiment O3, wherein the acid is selected from thegroup consisting of phosphoric acid, hydrochloric acid, acetic acid,citric acid, and combinations thereof.

Embodiment O5

The process of Embodiment O4, wherein the acid is phosphoric acid.

Embodiment O6

The process of any one of Embodiments O to O5, wherein the reaction ofstep a) is conducted in the presence of carbonyldiimidazole and a strongbase.

Embodiment O7

The process of any one of Embodiments O to O6, wherein the reaction ofstep a) is conducted in a solvent selected from the group consisting oftetrahydrofuran, water, and methyl tert-butyl ether.

Embodiment O8

The process of any one of Embodiments O to O7, wherein the reaction ofstep b) is conducted in a solvent selected from the group consisting oftetrahydrofuran, ethyl acetate, heptanes, ethanol, and water.

Embodiment O9

The process of any one of Embodiments O to O8, wherein the reaction ofstep c) is conducted in the presence of a base.

Embodiment O10

The process of any one of Embodiments O to O9, wherein the reaction ofstep c) is conducted in a solvent selected from the group consisting ofdimethylacetamide, tetrahydrofuran, dichloromethane, ethyl acetate, andheptanes, and combinations thereof.

Embodiment O11

The process of any one of Embodiments O to O10, wherein the reaction ofstep d) is conducted in a solvent selected from the group consisting ofacetonitrile, toluene, and combinations thereof.

Embodiment O12

The process of any one of Embodiments O to O11, further comprisingcontacting the reaction mixture formed in step d) with a hydroxide.

Embodiment O13

The process of Embodiment O12, wherein the hydroxide is sodiumhydroxide.

Embodiment O14

The process of any one of Embodiments O to O13, wherein the reaction ofstep e) is conducted in a solvent selected from the group consisting ofethanol, isopropyl acetate, and combinations thereof.

Embodiment O15

The process of any one of Embodiments O to O14, wherein step e)comprises contacting the compound of formula (VII) with an acid to formthe pharmaceutically acceptable salt of the compound of formula (VII).

Embodiment O16

The process of any one of Embodiments O to O15, wherein thepharmaceutically acceptable salt of the compound of formula (VII) isselected from the group consisting of:

Embodiment O17

The process of any one of Embodiments O to O16, wherein step e)comprises contacting the compound of formula (VI) with an acid to formthe pharmaceutically acceptable salt of the compound of formula (VII).

Embodiment O18

The process of any one of Embodiments O to O17, wherein thepharmaceutically acceptable salt of the compound of formula (VII) instep f) is selected from the group consisting of a compound of formula(VIIa), a compound of formula (VIIb), and a compound of formula (VIIc).

Embodiment O19

The process of any one of Embodiments O to O18, wherein the reaction ofstep f) is conducted in the presence of carbonyldiimidazole, dipotassiumphosphate, and potassium hydroxide.

Embodiment O20

The process of any one of Embodiments O to O19, further comprisingpreparing a crystalline hydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,the process comprising:

-   -   dissolving        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide        in a solvent or mixture of solvents; and    -   initiating crystallization to provide the crystalline hydrate;    -   wherein the crystalline hydrate is a hemihydrate.

Embodiment O21

A crystalline hydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideprepared by the process of Embodiment O20.

Embodiment O22

The process of any one of Embodiments O to O19, further comprisingpreparing a crystalline hydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,the process comprising:

dissolving(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamidein a solvent or mixture of solvents comprising an anti-solvent; and

maintaining the solvent or mixture of solvents at a temperature lessthan about 15° C. for an amount of time sufficient to initiatecrystallization of the crystalline hydrate;

wherein the crystalline hydrate has an X-ray powder diffraction patterncharacterized by peaks at 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees twotheta when measured at about 25° C. with monochromatic Kα1 radiation.

Embodiment O23

A crystalline hydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideprepared by the process of Embodiment O22.

Embodiment O24

The process of any one of Embodiments O to O19, further comprisingpreparing an amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,the process comprising dehydrating the crystalline hydrate produced inthe process of Embodiment O22 to provide the amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment O25

The process of any one of Embodiments O to O19, further comprisingpreparing an amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,the process comprising:

-   -   dissolving        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide        in a solvent or mixture of solvents; and    -   adjusting the pH of the solvent or mixture of solvents to a pH        greater than about 8 to initiate precipitation of the amorphous        freebase        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment O26

An amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideprepared by the process of Embodiment O24 or O25.

Embodiment O27

The process of any one of Embodiments O to O19, further comprisingpreparing a crystalline anhydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,the process comprising:

-   -   dissolving        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide        in a solvent or mixture of solvents, wherein the solvent or        mixture of solvents comprises less than about 0.15 wt. % of        water; and    -   initiating crystallization to provide the crystalline anhydrate.

Embodiment O28

A crystalline anhydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideprepared by the process of Embodiment O27.

Embodiment O29

The process of any one of Embodiments O to O19, wherein thepharmaceutically acceptable salt of the compound of formula (I) is thecompound of formula (Ib):

wherein the compound of formula (Ib) is prepared by:

-   -   (i) reacting carboxybenzyl-glycine ethyl ester with ethyl        acrylate to form a compound of formula (VIII):

-   -   (ii) protecting the compound of formula (VIII) to form a        compound of formula (IX):

wherein R³ is selected from the group consisting of CF₃SO₂—; CH₃SO₂—;and tosyl;

-   -   (iii) contacting the compound of formula (IX) with one of ethyl        boronic acid, ethyl magnesium bromide, or ethyl zinc chloride in        the presence of a catalyst to form a compound of formula (X):

-   -   (iv) hydrolyzing the compound of formula (X) to produce the        compound of formula (XI):

-   -   (v) converting the compound of formula (XI) to the compound of        formula (XII):

-   -   (vi) contacting the compound of formula (XII) with        dicyclohexylamine to form the compound of formula (Ib);        wherein Cbz is carboxybenzyl.

Embodiment O29a

The process of Embodiment O29, wherein the reaction of step (i) isconducted in the presence of a strong base.

Embodiment O29b

The process of Embodiment O29 or O29a, wherein the reaction of step (ii)is conducted in the presence of diisopropylethylamine.

Embodiment O29c

The process of any one of Embodiments O29 to O29b, wherein the catalystin step (iii) is a palladium catalyst.

Embodiment O29d

The process of any one of Embodiments O29 to O29c, wherein the compoundof formula (X) is contacted with an alkali metal hydroxide to form thecompound of formula (XI).

Embodiment O29e

The process of any one of Embodiments O29 to O29d, wherein the compoundof formula (XI) is contacted with a ruthenium catalyst to form thecompound of formula (XII).

Embodiment O30

The process of any one of Embodiments O to O19, wherein thepharmaceutically acceptable salt of the compound of formula (I) is thecompound of formula (Ia):

wherein the compound of formula (Ia) is prepared by:

-   -   (i) hydrogenating ethyl pent-2-ynoate with a Lindlar catalyst to        form (Z)-ethyl pent-2-enoate;    -   (ii) reacting (Z)-ethyl pent-2-enoate with        N-(methoxymethyl)-N-(trimethylsilyl methyl)benzylamine to form a        compound of formula (XIII)

-   -   (iii) deprotecting the compound of formula (XIII) to form a        compound of formula (XIV)

-   -   (iv) hydrolyzing the compound of formula (XIV) to form a        compound of formula (XV)

-   -   (v) reacting the compound of formula (XV) with        N-benzyloxycarbonyloxy succinimide to form a compound of formula        (XVI)

-   -   (vi) contacting the compound of formula (XVI) with        (R)-1-(naphthalene-1-yl)ethanamine to form the compound of        formula (Ia);        wherein Cbz is carboxybenzyl; Bn is benzyl; and Et is ethyl.

Embodiment O30a

The process of Embodiment O30, wherein the reaction of step (i) isconducted in a solvent selected from pyridine, tetrahydrofuran, andcombinations thereof.

Embodiment O30b

The process of Embodiment O30 or O30a, wherein the compound of formula(XIII) is deprotected by hydrogenating with a catalyst and hydrogen gas.

Embodiment O30c

The process of any one of Embodiments O30 to O30b, wherein the compoundof formula (XIV) is contacted with hydrochloric acid to form thecompound of formula (XV).

Embodiment P

A process for preparing(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,or a pharmaceutically acceptable salt thereof, the process comprising:

-   -   a) reacting a compound of formula (Ib)

with trimethylsulfoxonium chloride in the presence ofcarbonyldiimidazole and a strong base to form a compound of formula(IIa)

wherein Cbz is carboxybenzyl;

-   -   b) contacting the compound of formula (IIa) with lithium bromide        and a sulfonic acid to form a compound of formula (IIIa)

-   -   c) reacting the compound of formula (IIIa) with a compound of        formula (IVa)

in the presence of lithium tert-butoxide to produce a compound offormula (Va)

wherein R₂ is methyl or ethyl; and Ts is tosyl;

-   -   d) contacting the compound of formula (Va) with a perfluoro acid        anhydride and an organic base to form a compound of formula        (VIa)

-   -   e) deprotecting the compound of formula (VIa) to form a compound        of formula (VII)

-   -   f) contacting the compound of formula (VII) with hydrochloric        acid to form a compound of formula (VIIa)

-   -   g) reacting the compound of formula (VIIa) with        2,2,2-trifluoroethylamine in the presence of carbonyldiimidazole        to produce        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment P1

The process of Embodiment P, wherein:

-   -   the strong base of step a) is potassium tert-butoxide;    -   the sulfonic acid of step b) is selected from the group        consisting of methanesulfonic acid and p-toulenesulfonic acid;    -   the perfluoro acid anhydride of step d) is trifluoroacetic        anhydride;    -   the organic base of step d) is pyridine;    -   the compound of formula (VIa) is deprotected using hydrogen gas        and Pd(OH₂)/C; and    -   the reaction of step g) is conducted in the presence of        dipotassium phosphate and potassium hydroxide.

Embodiment P2

The process of Embodiment P or P1, further comprising contacting thecompound of formula (Ib) with an acid prior to reacting totrimethylsulfoxonium chloride.

Embodiment P3

The process of Embodiment P2, wherein the acid is selected from thegroup consisting of a mineral acid or an organic acid.

Embodiment P4

The process of Embodiment P3, wherein the acid is selected from thegroup consisting of phosphoric acid, hydrochloric acid, acetic acid,citric acid, and combinations thereof.

Embodiment P5

The process of Embodiment P4, wherein the acid is phosphoric acid.

Embodiment P6

The process of any one of Embodiments P to P5, further comprisingpreparing a crystalline hydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,the process comprising:

-   -   dissolving        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide        in a solvent or mixture of solvents; and    -   initiating crystallization to provide the crystalline hydrate;    -   wherein the crystalline hydrate is a hemihydrate.

Embodiment P7

A crystalline hydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideprepared by the process of Embodiment P6.

Embodiment P8

The process of any one of Embodiments P to P5, further comprisingpreparing a crystalline hydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,the process comprising:

-   -   dissolving        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide        in a solvent or mixture of solvents comprising an anti-solvent;        and    -   maintaining the solvent or mixture of solvents at a temperature        less than about 15° C. for an amount of time sufficient to        initiate crystallization of the crystalline hydrate;    -   wherein the crystalline hydrate has an X-ray powder diffraction        pattern characterized by peaks at 3.1±0.2, 9.3±0.2, and 12.0±0.2        degrees two theta when measured at about 25° C. with        monochromatic Kα1 radiation.

Embodiment P9

A crystalline hydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideprepared by the process of Embodiment P8.

Embodiment P10

The process of any one of Embodiments P to P5, further comprisingpreparing an amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,the process comprising dehydrating the crystalline hydrate produced inthe process of Embodiment P8 to provide the amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment P11

The process of any one of Embodiments P to P5, further comprisingpreparing an amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,the process comprising:

-   -   dissolving        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide        in a solvent or mixture of solvents; and    -   adjusting the pH of the solvent or mixture of solvents to a pH        greater than about 8 to initiate precipitation of the amorphous        freebase        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment P12

An amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideprepared by the process of Embodiment P10 or P11.

Embodiment P13

The process of any one of Embodiments P to P5, further comprisingpreparing a crystalline anhydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,the process comprising:

-   -   dissolving        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide        in a solvent or mixture of solvents, wherein the solvent or        mixture of solvents comprises less than about 0.15 wt. % of        water; and initiating crystallization to provide the crystalline        anhydrate.

Embodiment P14

A crystalline anhydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideprepared by the process of Embodiment P13.

Embodiment Q

A process for preparing(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,or a pharmaceutically acceptable salt thereof, the process comprising:

-   -   a) converting a compound of formula (XIa):

-   -   to a compound of formula (I):

-   -   wherein PG is a protecting group;    -   b) reacting the compound of formula (I) with        trimethylsulfoxonium chloride to form a compound of formula (II)

-   -   c) contacting the compound of formula (II) with an anhydrous        source of HBr or HCl to form a compound of formula (III)

-   -   wherein X is Br or Cl    -   d) reacting the compound of formula (III) with a compound of        formula (IV)

-   -   to produce a compound of formula (V)

-   -   wherein R₁ is selected from the group consisting of alkyl, aryl,        and —OR₂; R₂ is alkyl; and Ts is tosyl;    -   e) contacting the compound of formula (V) with a perfluoro acid        anhydride and an organic base to form a compound of formula (VI)

-   -   f) deprotecting the compound of formula (VI) and forming a        pharmaceutically acceptable salt of the compound of formula        (VII):

and

-   -   g) reacting the pharmaceutically acceptable salt of the compound        of formula (VII) with 2,2,2-trifluoroethylamine to produce        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment Q1

The process of Embodiment Q, wherein step f) comprises contacting thecompound of formula (VII) with an acid to form the pharmaceuticallyacceptable salt of the compound of formula (VII).

Embodiment Q2

The process of Embodiment Q or Q1, wherein the protecting group iscarboxybenzyl.

Embodiment Q3

The process of any one of Embodiments Q to Q2, wherein the anhydroussource of HBr or HCl comprises no more than 0.2% water (by volume).

Embodiment Q4

The process of any one of Embodiments Q to Q3, wherein step a) isconducted in a solvent selected from the group consisting of methanol,trimethylamine, and combinations thereof.

Embodiment Q5

The process of any one of Embodiments Q to Q4, wherein step b) comprisesreacting the compound of formula (I) with trimethylsulfoxonium chloridein the presence of carbonyldiimidazole and a strong base to form thecompound of formula (II).

Embodiment Q6

The process of Embodiment Q5, wherein the base is selected from thegroup consisting of potassium tert-butoxide, sodium tert-butoxide, andcombinations thereof.

Embodiment Q7

The process of any one of Embodiments Q to Q6, wherein step b) isconducted in a solvent selected from the group consisting oftetrahydrofuran, water, methyl tert-butyl ether, and combinationsthereof.

Embodiment Q8

The process of any one of Embodiments Q to Q7, wherein step c) isconducted in tetrahydrofuran, and comprises contacting the compound offormula (II) with an anhydrous source of HBr to form the compound offormula (III).

Embodiment Q9

The process of Embodiment Q8, wherein the anhydrous source of HBr isHBr/HOAc.

Embodiment Q10

The process of any one of Embodiments Q to Q9, wherein step d) comprisesreacting the compound of formula (III) with the compound of formula (IV)in the presence of lithium tert-butoxide to produce the compound offormula (V).

Embodiment Q11

The process of any one of Embodiments Q to Q10, wherein the reaction ofstep e) is conducted in a solvent selected from the group consisting ofacetonitrile, toluene, and combinations thereof.

Embodiment Q12

The process of any one of Embodiments Q to Q11, further comprisingcontacting the reaction mixture formed in step d) with a hydroxide.

Embodiment Q13

The process of Embodiment Q12, wherein the hydroxide is sodiumhydroxide.

Embodiment Q14

The process of any one of Embodiments Q to Q13, wherein the reaction ofstep f) is conducted in a solvent selected from the group consisting ofethanol, isopropyl acetate, and combinations thereof.

Embodiment Q15

The process of any one of Embodiments Q to Q14, wherein step f)comprises contacting the compound of formula (VII) with an acid to formthe pharmaceutically acceptable salt of the compound of formula (VII).

Embodiment Q16

The process of any one of Embodiments Q to Q14, wherein step f)comprises contacting the compound of formula (VI) with an acid to formthe pharmaceutically acceptable salt of the compound of formula (VII).

Embodiment Q17

The process of any one of Embodiments Q to Q16, wherein thepharmaceutically acceptable salt of the compound of formula (VII) isselected from the group consisting of:

Embodiment Q18

The process of any one of Embodiments Q to Q17, further comprisingpreparing a crystalline hydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,the process comprising:

-   -   dissolving        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide        in a solvent or mixture of solvents; and    -   initiating crystallization to provide the crystalline hydrate;    -   wherein the crystalline hydrate is a hemihydrate.

Embodiment Q19

A crystalline hydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideprepared by the process of Embodiment Q18.

Embodiment Q20

The process of any one of Embodiments Q to Q17, further comprisingpreparing a crystalline hydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,the process comprising:

-   -   dissolving        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide        in a solvent or mixture of solvents comprising an anti-solvent;        and    -   maintaining the solvent or mixture of solvents at a temperature        less than about 15° C. for an amount of time sufficient to        initiate crystallization of the crystalline hydrate;    -   wherein the crystalline hydrate has an X-ray powder diffraction        pattern characterized by peaks at 3.1±0.2, 9.3±0.2, and 12.0±0.2        degrees two theta when measured at about 25° C. with        monochromatic Kα1 radiation.

Embodiment Q21

A crystalline hydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideprepared by the process of Embodiment Q20.

Embodiment Q22

The process of any one of Embodiments Q to Q17, further comprisingpreparing an amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,the process comprising dehydrating the crystalline hydrate produced inthe process of Embodiment Q20 to provide the amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment Q23

The process of any one of Embodiments Q to Q17, further comprisingpreparing an amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,the process comprising:

-   -   dissolving        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide        in a solvent or mixture of solvents; and    -   adjusting the pH of the solvent or mixture of solvents to a pH        greater than about 8 to initiate precipitation of the amorphous        freebase        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

Embodiment Q24

An amorphous freebase(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideprepared by the process of Embodiment Q22 or Q23.

Embodiment Q25

The process of any one of Embodiments Q to Q17, further comprisingpreparing a crystalline anhydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide,the process comprising:

-   -   dissolving        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide        in a solvent or mixture of solvents, wherein the solvent or        mixture of solvents comprises less than about 0.15 wt. % of        water; and initiating crystallization to provide the crystalline        anhydrate.

Embodiment Q26

A crystalline anhydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideprepared by the process of Embodiment Q25.

Embodiment R

A compound of formula (II):

-   -   wherein PG is a protecting group.

Embodiment R1

The compound of Embodiment R, wherein the protecting group is selectedfrom the group consisting of carboxybenzyl, p-methoxybenzyl carbonyl,benzyl, p-methoxybenzyl, and 3,4-dimethoxybenzyl.

Embodiment R2

A process for preparing a compound of formula (II):

-   -   the process comprising reacting a compound of formula (I)

-   -   or a pharmaceutically acceptable salt thereof with        trimethylsulfoxonium chloride to form the compound of formula        (II),    -   wherein PG is a protecting group.

Embodiment R2a

The process of Embodiment R2, wherein the protecting group is selectedfrom the group consisting of carboxybenzyl, p-methoxybenzyl carbonyl,benzyl, p-methoxybenzyl, and 3,4-dimethoxybenzyl.

Embodiment R2b

The process of Embodiment R2 or R2a, wherein the pharmaceuticallyacceptable salt of the compound of formula (I) is selected from thegroup consisting of a compound of formula (Ia) and a compound of formula(Ib)

Embodiment R2c

The process of any one of embodiments R2 to R2b, wherein the reaction isconducted in the presence of carbonyldiimidazole and a strong base.

Embodiment R2d

The process of any one of embodiments R2 to R2c, wherein the reaction isconducted in the presence of phosphoric acid.

Embodiment R2e

The process of any one of embodiments R2 to R2d, wherein the reaction isconducted in a solvent selected from the group consisting oftetrahydrofuran, water, and methyl tert-butyl ether.

Embodiment R3

A process for preparing a compound of formula (II):

-   -   the process comprising    -   a) converting a compound of formula (XIa):

-   -   to a compound of formula (I):

-   -   wherein PG is a protecting group; and    -   b) reacting the compound of formula (I) with        trimethylsulfoxonium chloride to form the compound of formula        (II).

Embodiment R3a

The process of Embodiment R3, wherein the reaction of step b) isconducted in the presence of carbonyldiimidazole and a strong base.

Embodiment S

A process for the preparation of a compound of formula (III):

-   -   the process comprising contacting a compound of formula (II)

-   -   with LiX and a sulfonic acid to form the compound of formula        (III);    -   wherein PG is a protecting group; and X is Br or Cl.

Embodiment S1

The process of Embodiment S, wherein the compound of formula (II) isformed by reacting a compound of formula (I)

-   -   or a pharmaceutically acceptable salt thereof with        trimethylsulfoxonium chloride.

Embodiment S2

The process of Embodiment S1, wherein the pharmaceutically acceptablesalt of the compound of formula (I) is selected from the groupconsisting of a compound of formula (Ia) and a compound of formula (Ib)

Embodiment S3

The process of Embodiment S1 or S2, wherein the compound or thepharmaceutically acceptable salt of formula (I) is reacted withtrimethylsulfoxonium chloride in the presence of carbonyldiimidazole anda strong base.

Embodiment S4

A process for the preparation of a compound of formula (III):

-   -   the process comprising contacting a compound of formula (II)

-   -   with an anhydrous source of HBr or HCl to form a compound of        formula (III), wherein PG is a protecting group, and X is Br or        Cl.

Embodiment S4a

The process of Embodiment S4, wherein the compound of formula (II) isformed by converting a compound of formula (XIa):

-   -   to a compound of formula (I):

-   -   wherein PG is a protecting group; and    -   reacting the compound of formula (I) with trimethylsulfoxonium        chloride to form the compound of formula (II).

Embodiment S4b

The process of Embodiment S4 or S4a, wherein the compound of formula(II) is contacted with an anhydrous source of HBr to form the compoundof formula (III).

Embodiment S4c

The process of Embodiment S4b, wherein the anhydrous source of HBr isHBr/HOAc.

Embodiment T

A compound of formula (Va)

-   -   wherein R₂ is methyl or ethyl; Ts is tosyl; and Cbz is        carboxybenzyl.

Embodiment T1

A process for preparing a compound of formula (V)

-   -   the process comprising:    -   a) reacting a compound of formula (I)

-   -   or a pharmaceutically acceptable salt thereof with        trimethylsulfoxonium chloride to form a compound of formula (II)

-   -   b) contacting the compound of formula (II) with LiX and a        sulfonic acid to form a compound of formula (III)

-   -   c) reacting the compound of formula (III) with a compound of        formula (IV)

-   -   to produce the compound of formula (V);    -   wherein:    -   PG is a protecting group;    -   X is Br or Cl;

R₁ is selected from the group consisting of alkyl, aryl, and —OR₂;

-   -   R₂ is alkyl; and    -   Ts is tosyl.

Embodiment T1a

The process of Embodiment T1, wherein the pharmaceutically acceptablesalt of the compound of formula (I) is selected from the groupconsisting of a compound of formula (Ia) and a compound of formula (Ib)

Embodiment T1b

The process of Embodiment T1 or T1a, wherein the reaction of step a) isconducted in the presence of carbonyldiimidazole and a strong base.

Embodiment T1c

The process of any one of Embodiments T1 to T1b, wherein the reaction ofstep c) is conducted in the presence of a base selected from the groupconsisting of lithium tert-butoxide, sodium tert-butoxide, andcombinations thereof.

Embodiment T2

A process for preparing a compound of formula (V)

-   -   the process comprising:    -   a) converting a compound of formula (XIa):

-   -   to a compound of formula (I):

-   -   wherein PG is a protecting group;    -   b) reacting the compound of formula (I) with        trimethylsulfoxonium chloride to form a compound of formula (II)

-   -   c) contacting the compound of formula (II) with an anhydrous        source of HBr or HCl to form a compound of formula (III)

-   -   wherein X is Br or Cl    -   d) reacting the compound of formula (III) with a compound of        formula (IV)

-   -   to produce a compound of formula (V)

-   -   wherein R₁ is selected from the group consisting of alkyl, aryl,        and —OR₂; R₂ is alkyl; and Ts is tosyl.

Embodiment T2a

The process of Embodiment T2, wherein the compound of formula (II) iscontacted with an anhydrous source of HBr to form the compound offormula (III).

Embodiment T2b

The process of Embodiment T2a, wherein the anhydrous source of HBr isHBr/HOAc.

Embodiment T3

A process for preparing a crystalline compound of formula (V)

-   -   the process comprising:    -   a) reacting a compound of formula (III)

-   -   with a compound of formula (IV):

-   -   to produce the compound of formula (V);    -   wherein:    -   PG is a protecting group;    -   X is Br or Cl    -   R₁ is —OR₂;    -   R₂ is methyl or ethyl; and    -   Ts is tosyl.

Embodiment U

A compound of formula (IVa):

-   -   wherein R₂ is methyl or ethyl, and Ts is tosyl.

Embodiment V

A compound of formula (VII):

or a pharmaceutically acceptable salt thereof.

Embodiment V1

The compound of Embodiment V, wherein the pharmaceutically acceptablesalt of the compound of formula (VII) is selected from the groupconsisting of:

Embodiment W

A process for preparing a compound of formula (Ib)

-   -   wherein Cbz is carboxybenzyl, the process comprising:    -   (i) reacting carboxybenzyl-glycine ethyl ester with ethyl        acrylate to form a compound of formula (VIII):

-   -   (ii) protecting the compound of formula (VIII) to form a        compound of formula (IX):

-   -   wherein R³ is selected from the group consisting of CF₃SO₂—;        CH₃SO₂—; and tosyl;    -   (iii) contacting the compound of formula (IX) with one of ethyl        boronic acid, ethyl magnesium bromide, or ethyl zinc chloride in        the presence of a catalyst to form a compound of formula (X):

-   -   (iv) hydrolyzing the compound of formula (X) to produce the        compound of formula (XI):

-   -   (v) converting the compound of formula (XI) to the compound of        formula (XII):

-   -   (vi) contacting the compound of formula (XII) with        dicyclohexylamine to form the compound of formula (Ib).

Embodiment W1

The process of Embodiment W, wherein the reaction of step (i) isconducted in the presence of a strong base.

Embodiment W2

The process of Embodiment W or W1, wherein the reaction of step (i) isconducted in an organic solvent.

Embodiment W3

The process of any one of Embodiments W to W2, wherein the reaction ofstep (ii) is conducted in the presence of diisopropylethylamine.

Embodiment W4

The process of any one of Embodiments W to W3, wherein the reaction ofstep (ii) is conducted in a solvent selected from the group consistingof triethylamine, N-methylmorpholine, pyridine, diisopropyl ether, andcombinations thereof.

Embodiment W5

The process of any one of Embodiments W to W4, wherein the reaction ofstep (iii) is conducted in a buffer selected from the group consistingof potassium carbonate, sodium carbonate, potassium phosphate tribasic,and combinations thereof.

Embodiment W6

The process of any one of Embodiments W to W5, wherein the reaction ofstep (iii) is conducted in a solvent selected from the group consistingof toluene, water, dioxane, tetrahydrofuran, and combinations thereof.

Embodiment W7

The process of any one of Embodiments W to W6, wherein the compound offormula (X) is contacted with an alkali metal hydroxide to form thecompound of formula (XI).

Embodiment W8

The process of any one of Embodiments W to W7, wherein the compound offormula (XI) is contacted with a ruthenium catalyst to form the compoundof formula (XII).

Embodiment W9

The process of any one of Embodiments W to W8, wherein:

-   -   the reaction of step (i) is conducted in the presence of sodium        tert-butoxide;    -   the reaction of step (ii) is conducted in the presence of        diisopropylethylamine;    -   the catalyst in step (iii) PdCl₂(dppf);    -   the reaction of step (iii) is conducted in potassium carbonate;    -   the compound of formula (X) is contacted with sodium hydroxide        to form the compound of formula (XI); and    -   the compound of formula (XI) is contacted with a ruthenium        catalyst to form the compound of formula (XII).

Embodiment X

The dicyclohexylamine salt of(3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate.

Embodiment Y

A method of treating an adult subject having moderate to severely activerheumatoid arthritis, the method comprising administering to thesubject:

-   -   a) about 7.5 mg of Compound 1 freebase, or a pharmaceutically        acceptable salt thereof, or a crystalline hydrate or a        crystalline anhydrate of Compound 1 in an amount sufficient to        deliver to the subject about 7.5 mg of Compound 1 freebase        equivalent; or    -   b) about 15 mg of Compound 1 freebase, or a pharmaceutically        acceptable salt thereof, or a crystalline hydrate or a        crystalline anhydrate of Compound 1 in an amount sufficient to        deliver to the subject about 15 mg of Compound 1 freebase        equivalent; or    -   c) about 30 mg of Compound 1 freebase, or a pharmaceutically        acceptable salt thereof, or a crystalline hydrate or a        crystalline anhydrate of Compound 1 in an amount sufficient to        deliver to the subject about 30 mg of Compound 1 freebase        equivalent; or    -   d) about 45 mg of Compound 1 freebase, or a pharmaceutically        acceptable salt thereof, or a crystalline hydrate or a        crystalline anhydrate of Compound 1 in an amount sufficient to        deliver to the subject about 45 mg of Compound 1 freebase        equivalent.

Embodiment Y1

The method of Embodiment Y, wherein the crystalline hydrate is ahemihydrate.

Embodiment Y2

The method of Embodiment Y1, wherein the crystalline hydrate is FreebaseHydrate Form C.

Embodiment Y3

The method of Embodiment Y, wherein the crystalline anhydrate isFreebase Anhydrate Form D.

Embodiment Y4

The method of any one of Embodiments Y to Y3, wherein the freebase, orthe pharmaceutically acceptable salt thereof, or the hydrate, or theanhydrate is in a once daily extended release formulation.

Embodiment Y5

A pharmaceutical composition for use in treating an adult subject havingmoderate to severely active rheumatoid arthritis, wherein thepharmaceutical composition comprises:

-   -   a) about 7.5 mg of Compound 1 freebase, or a pharmaceutically        acceptable salt thereof, or a crystalline hydrate or a        crystalline anhydrate of Compound 1 in an amount sufficient to        deliver to the subject about 7.5 mg of Compound 1 freebase        equivalent; or    -   b) about 15 mg of Compound 1 freebase, or a pharmaceutically        acceptable salt thereof, or a crystalline hydrate or a        crystalline anhydrate of Compound 1 in an amount sufficient to        deliver to the subject about 15 mg of Compound 1 freebase        equivalent; or    -   c) about 30 mg of Compound 1 freebase, or a pharmaceutically        acceptable salt thereof, or a crystalline hydrate or a        crystalline anhydrate of Compound 1 in an amount sufficient to        deliver to the subject about 30 mg of Compound 1 freebase        equivalent; or    -   d) about 45 mg of Compound 1 freebase, or a pharmaceutically        acceptable salt thereof, or a crystalline hydrate or a        crystalline anhydrate of Compound 1 in an amount sufficient to        deliver to the subject about 45 mg of Compound 1 freebase        equivalent.

In certain aspects of Embodiment Y5, the use comprises administering tothe subject the pharmaceutical composition,

Embodiment Y6

The method or pharmaceutical composition of any one of Embodiments Y toY5, wherein the adult subject achieves ACR20 response at week 12 of saidtreating.

Embodiment Y7

The method or pharmaceutical composition of any one of Embodiments Y toY6, wherein the adult subject achieves ACR20 response at week 8 of saidtreating.

Embodiment Y8

The method or pharmaceutical composition of any one of Embodiments Y toY7, wherein the adult subject achieves ACR20 response at week 6 of saidtreating.

Embodiment Y9

The method or pharmaceutical composition of any one of Embodiments Y toY8, wherein the adult subject achieves ACR20 response at week 4 of saidtreating.

Embodiment Y10

The method or pharmaceutical composition of any one of Embodiments Y toY9, wherein the adult subject achieves ACR20 response at week 2 of saidtreating.

Embodiment Y11

The method or pharmaceutical composition of any one of Embodiments Y toY10, wherein the adult subject achieves ACR50 response at week 12 ofsaid treating.

Embodiment Y12

The method or pharmaceutical composition of any one of Embodiments Y toY11, wherein the adult subject achieves ACR50 response at week 8 of saidtreating.

Embodiment Y13

The method or pharmaceutical composition of any one of Embodiments Y toY12, wherein the adult subject achieves ACR50 response at week 6 of saidtreating.

Embodiment Y14

The method or pharmaceutical composition of any one of Embodiments Y toY13, wherein the adult subject achieves ACR50 response at week 4 of saidtreating.

Embodiment Y15

The method or pharmaceutical composition of any one of Embodiments Y toY14, wherein the adult subject achieves ACR50 response at week 2 of saidtreating.

Embodiment Y16

The method or pharmaceutical composition of any one of Embodiments Y toY15, wherein the adult subject achieves ACR70 response at week 12 ofsaid treating.

Embodiment Y17

The method or pharmaceutical composition of any one of Embodiments Y toY16, wherein the adult subject achieves ACR70 response at week 8 of saidtreating.

Embodiment Y18

The method or pharmaceutical composition of any one of Embodiments Y toY17, wherein the adult subject achieves ACR70 response at week 6 of saidtreating.

Embodiment Y19

The method or pharmaceutical composition of any one of Embodiments Y toY18, wherein the adult subject achieves ACR70 response at week 4 of saidtreating.

Embodiment Y20

The method or pharmaceutical composition of any one of Embodiments Y toY19, wherein the adult subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 12 of said treating.

Embodiment Y21

The method or pharmaceutical composition of any one of Embodiments Y toY20, wherein the adult subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 8 of said treating.

Embodiment Y22

The method or pharmaceutical composition of any one of Embodiments Y toY21, wherein the adult subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 6 of said treating.

Embodiment Y23

The method or pharmaceutical composition of any one of Embodiments Y toY22, wherein the adult subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 4 of said treating.

Embodiment Y24

The method or pharmaceutical composition of any one of Embodiments Y toY23, wherein the adult subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 2 of said treating.

Embodiment Y25

The method or pharmaceutical composition of any one of Embodiments Y toY5, wherein the adult subject has had an inadequate response ortolerance to one or more disease-modifying antirheumatic drugs (DMARDS).

Embodiment Y26

The method or pharmaceutical composition Embodiment Y25, wherein theDMARD is a conventional synthetic DMARD or a biologic DMARD.

Embodiment Y27

The method or pharmaceutical composition Embodiment Y25, wherein theDMARD is an anti-TNF biologic DMARD.

Embodiment Y28

The method or pharmaceutical composition of Embodiment Y27, wherein theadult subject has received the anti-TNF biologic DMARD for at leastthree months prior to said treating.

Embodiment Y29

The method or pharmaceutical composition of any one of Embodiments Y25to Y28, wherein the DMARD is methotrexate.

Embodiment Y30

The method or pharmaceutical composition of Embodiment Y29, wherein theadult subject has received the methotrexate for at least three monthsprior to said treating.

Embodiment Y31

The method or pharmaceutical composition of any one of Embodiments Y25to Y30, wherein the adult subject is administered stable backgroundmethotrexate for at least three months prior to said treating.

Embodiment Y32

The method or pharmaceutical composition of any one of Embodiments Y25to Y31, wherein the adult subject is administered stable backgroundmethotrexate during said treating.

Embodiment Y33

The method or pharmaceutical composition of any one of Embodiments Y25to Y32, wherein the adult subject receives a supplement of folic acidfor at least four weeks prior to said treating.

Embodiment Y34

The method or pharmaceutical composition of any one of Embodiments Y25to Y33, wherein the adult subject is administered a supplement of folicacid during said treating.

Embodiment Y35

The method or pharmaceutical composition of any one of Embodiments Y25to Y34, wherein the adult subject achieves ACR20 response at week 12 ofsaid treating.

Embodiment Y36

The method or pharmaceutical composition of any one of Embodiments Y25to Y35, wherein the adult subject achieves ACR20 response at week 8 ofsaid treating.

Embodiment Y37

The method or pharmaceutical composition of any one of Embodiments Y25to Y36, wherein the adult subject achieves ACR20 response at week 6 ofsaid treating.

Embodiment Y38

The method or pharmaceutical composition of any one of Embodiments Y25to Y37, wherein the adult subject achieves ACR20 response at week 4 ofsaid treating.

Embodiment Y39

The method or pharmaceutical composition of any one of Embodiments Y25to Y38, wherein the adult subject achieves ACR20 response at week 2 ofsaid treating.

Embodiment Y40

The method or pharmaceutical composition of any one of Embodiments Y25to Y39, wherein the adult subject achieves ACR50 response at week 12 ofsaid treating.

Embodiment Y41

The method or pharmaceutical composition of any one of Embodiments Y25to Y40, wherein the adult subject achieves ACR50 response at week 8 ofsaid treating.

Embodiment Y42

The method or pharmaceutical composition of any one of Embodiments Y25to Y41, wherein the adult subject achieves ACR50 response at week 6 ofsaid treating.

Embodiment Y43

The method or pharmaceutical composition of any one of Embodiments Y25to Y42, wherein the adult subject achieves ACR50 response at week 4 ofsaid treating.

Embodiment Y44

The method or pharmaceutical composition of any one of Embodiments Y25to Y43, wherein the adult subject achieves ACR50 response at week 2 ofsaid treating.

Embodiment Y45

The method or pharmaceutical composition of any one of Embodiments Y25to Y44, wherein the adult subject achieves ACR70 response at week 12 ofsaid treating.

Embodiment Y46

The method or pharmaceutical composition of any one of Embodiments Y25to Y45, wherein the adult subject achieves ACR70 response at week 8 ofsaid treating.

Embodiment Y47

The method or pharmaceutical composition of any one of Embodiments Y25to Y46, wherein the adult subject achieves ACR70 response at week 6 ofsaid treating.

Embodiment Y48

The method or pharmaceutical composition of any one of Embodiments Y25to Y47, wherein the adult subject achieves ACR70 response at week 4 ofsaid treating.

Embodiment Y49

The method or pharmaceutical composition of any one of Embodiments Y25to Y48, wherein the adult subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 12 of said treating.

Embodiment Y50

The method or pharmaceutical composition of any one of Embodiments Y25to Y49, wherein the adult subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 8 of said treating.

Embodiment Y51

The method or pharmaceutical composition of any one of Embodiments Y25to Y50, wherein the adult subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 6 of said treating.

Embodiment Y52

The method or pharmaceutical composition of any one of Embodiments Y25to Y51, wherein the adult subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 4 of said treating.

Embodiment Y53

The method or pharmaceutical composition of any one of Embodiments Y25to Y52, wherein the adult subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 2 of said treating.

Embodiment Y54

The method or pharmaceutical composition of any one of Embodiments Y25to Y53, wherein the adult subject is also administered a conventionalsynthetic or a biologic DMARD.

Embodiment Y55

The method or pharmaceutical composition Embodiment Y54, wherein theDMARD is methotrexate.

Embodiment Y56

The method or pharmaceutical composition of Embodiment Y54 or Y55,wherein the adult subject achieves ACR20 response at week 12 of saidtreating.

Embodiment Y57

The method or pharmaceutical composition of any one of Embodiments Y54to Y56, wherein the adult subject achieves ACR20 response at week 8 ofsaid treating.

Embodiment Y58

The method or pharmaceutical composition of any one of Embodiments Y54to Y57, wherein the adult subject achieves ACR20 response at week 6 ofsaid treating.

Embodiment Y59

The method or pharmaceutical composition of any one of Embodiments Y54to Y58, wherein the adult subject achieves ACR20 response at week 4 ofsaid treating.

Embodiment Y60

The method or pharmaceutical composition of any one of Embodiments Y54to Y59, wherein the adult subject achieves ACR20 response at week 2 ofsaid treating.

Embodiment Y61

The method or pharmaceutical composition of any one of Embodiments Y54to Y60, wherein the adult subject achieves ACR50 response following saidtreating.

Embodiment Y62

The method or pharmaceutical composition of any one of Embodiments Y54to Y61, wherein the adult subject achieves ACR50 response at week 12 ofsaid treating.

Embodiment Y63

The method or pharmaceutical composition of any one of Embodiments Y54to Y62, wherein the adult subject achieves ACR50 response at week 8 ofsaid treating.

Embodiment Y64

The method or pharmaceutical composition of any one of Embodiments Y54to Y63, wherein the adult subject achieves ACR50 response at week 6 ofsaid treating.

Embodiment Y65

The method or pharmaceutical composition of any one of Embodiments Y54to Y64, wherein the adult subject achieves ACR50 response at week 4 ofsaid treating.

Embodiment Y66

The method or pharmaceutical composition of any one of Embodiments Y54to Y65, wherein the adult subject achieves ACR50 response at week 2 ofsaid treating.

Embodiment Y67

The method or pharmaceutical composition of any one of Embodiments Y54to Y66, wherein the adult subject achieves ACR70 response following saidtreating.

Embodiment Y68

The method or pharmaceutical composition of any one of Embodiments Y54to Y67, wherein the adult subject achieves ACR70 response at week 12 ofsaid treating.

Embodiment Y69

The method or pharmaceutical composition of any one of Embodiments Y54to Y68, wherein the adult subject achieves ACR70 response at week 8 ofsaid treating.

Embodiment Y70

The method or pharmaceutical composition of any one of Embodiments Y54to Y69, wherein the adult subject achieves ACR70 response at week 6 ofsaid treating.

Embodiment Y71

The method or pharmaceutical composition of any one of Embodiments Y54to Y70, wherein the adult subject achieves ACR70 response at week 4 ofsaid treating.

Embodiment Y72

The method or pharmaceutical composition of any one of Embodiments Y54to Y71, wherein the adult subject achieves ACR70 response at week 2 ofsaid treating.

Embodiment Y73

The method or pharmaceutical composition of any one of Embodiments Y toY72, wherein the arthritis is further treated by alleviating at leastone symptom selected from the group consisting of bone erosion,cartilage erosion, inflammation and vascularity.

Embodiment Y74

The method or pharmaceutical composition of Embodiment Y73, wherein thearthritis is further treated by alleviating at least one symptomselected from the group consisting of joint distortion, swelling, jointdeformation, ankyloses on flexion and severely impaired movement.

Embodiment Y75

The method or pharmaceutical composition of any one of Embodiments Y toY74, wherein the crystalline hydrate or crystalline anhydrate ofCompound 1 is administered in an amount sufficient to deliver to thesubject 7.5 mg of Compound 1 freebase equivalent.

Embodiment Y76

The method or pharmaceutical composition of any one of Embodiments Y toY74, wherein the crystalline hydrate or the crystalline anhydrate ofCompound 1 is administered in an amount sufficient to deliver to thesubject 15 mg of Compound 1 freebase equivalent.

Embodiment Y77

The method or pharmaceutical composition of any one of Embodiments Y toY74, wherein the crystalline hydrate or the crystalline anhydrate ofCompound 1 is administered in an amount sufficient to deliver to thesubject 30 mg of Compound 1 freebase equivalent.

Embodiment Y78

The method or pharmaceutical composition of any one of Embodiments Y toY74, wherein the crystalline hydrate or the crystalline anhydrate ofCompound 1 is administered in an amount sufficient to deliver to thesubject 45 mg of Compound 1 freebase equivalent.

Embodiment Z

A method of treating structural damage associated with rheumatoidarthritis in an adult subject, the method comprising administering tothe subject:

-   -   a) about 7.5 mg per day of        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide        (Compound 1) freebase or a pharmaceutically acceptable salt        thereof, or a crystalline hydrate or crystalline anhydrate of        Compound 1 in an amount sufficient to deliver to the subject        about 7.5 mg per day of Compound 1 freebase equivalent; or    -   b) about 15 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 15 mg per day of        Compound 1 freebase equivalent; or    -   c) about 30 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 30 mg per day of        Compound 1 freebase equivalent; or    -   d) about 45 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 45 mg per day of        Compound 1 freebase equivalent;    -   such that the structural damage in the adult subject is        inhibited or lessened.

Embodiment Z1

A pharmaceutical composition for use in treating structural damageassociated with rheumatoid arthritis in an adult subject, wherein thepharmaceutical composition comprises:

-   -   a) about 7.5 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 7.5 mg per day of        Compound 1 freebase equivalent; or    -   b) about 15 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 15 mg per day of        Compound 1 freebase equivalent; or    -   c) about 30 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 30 mg per day of        Compound 1 freebase equivalent; or    -   d) about 45 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 45 mg per day of        Compound 1 freebase equivalent;    -   such that the structural damage in the adult subject is        inhibited or lessened. In certain aspects of Embodiment Z1, the        use comprising administering the pharmaceutical composition to        the subject,

Embodiment Z2

A method of treating structural damage associated with rheumatoidarthritis in an adult subject, the method comprising administering tothe subject about 7.5 mg per day of Compound 1 freebase or apharmaceutically acceptable salt thereof, or a crystalline hydrate orcrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 15 mg per day of Compound 1 freebase equivalent,such that the structural damage in the adult subject is inhibited orlessened

Embodiment Z3

The method of Embodiment Z2, comprising administering the crystallinehydrate or crystalline anhydrate of Compound 1 in an amount sufficientto deliver to the subject 7.5 mg of Compound 1 freebase equivalent.

Embodiment Z4

A method of treating structural damage associated with rheumatoidarthritis in an adult subject, the method comprising administering tothe subject about 15 mg per day of Compound 1 freebase or apharmaceutically acceptable salt thereof, or a crystalline hydrate orcrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 15 mg per day of Compound 1 freebase equivalent,such that the structural damage in the adult subject is inhibited orlessened.

Embodiment Z5

The method of Embodiment Z4, comprising administering the crystallinehydrate or crystalline anhydrate of Compound 1 in an amount sufficientto deliver to the subject 15 mg of Compound 1 freebase equivalent.

Embodiment Z6

A method of treating structural damage associated with rheumatoidarthritis in an adult subject, the method comprising administering tothe subject about 30 mg per day of Compound 1 freebase or apharmaceutically acceptable salt thereof, or a crystalline hydrate orcrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 30 mg per day of Compound 1 freebase equivalent,such that the structural damage in the adult subject is inhibited orlessened.

Embodiment Z7

The method of Embodiment Z6, comprising administering the crystallinehydrate or crystalline anhydrate of Compound 1 in an amount sufficientto deliver to the subject 30 mg of Compound 1 freebase equivalent.

Embodiment Z8

A method of treating structural damage associated with rheumatoidarthritis in an adult subject, the method comprising administering tothe subject about 45 mg per day of Compound 1 freebase or apharmaceutically acceptable salt thereof, or a crystalline hydrate orcrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 45 mg per day of Compound 1 freebase equivalent,such that the structural damage in the adult subject is inhibited orlessened.

Embodiment Z9

The method of Embodiment Z8, comprising administering the crystallinehydrate or crystalline anhydrate of Compound 1 in an amount sufficientto deliver to the subject 45 mg of Compound 1 freebase equivalent.

Embodiment Z10

The method or composition of any one of Embodiments Z to Z9, wherein thehydrate is a hemihydrate.

Embodiment Z11

The method or composition of Embodiment Z10, wherein the hydrate isFreebase Hydrate Form C.

Embodiment Z12

The method or composition of any one of Embodiments Z to Z9, wherein theanhydrate is Freebase Anhydrate Form D.

Embodiment Z13

The method or composition of any one of Embodiments Z to Z12, whereinthe freebase or the hydrate or the anhydrate is in a once daily extendedrelease formulation.

Embodiment AA

A method of treating moderate to severely active rheumatoid arthritis inan adult subject, the method comprising administering to the subject:

-   -   a) about 7.5 mg per day of        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide        (Compound 1) freebase or a pharmaceutically acceptable salt        thereof, or a crystalline hydrate or crystalline anhydrate of        Compound 1 in an amount sufficient to deliver to the subject        about 7.5 mg per day of Compound 1 freebase equivalent; or    -   b) about 15 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 15 mg per day of        Compound 1 freebase equivalent; or    -   c) about 30 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 30 mg per day of        Compound 1 freebase equivalent; or    -   d) about 45 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 45 mg per day of        Compound 1 freebase equivalent; and    -   wherein the subject has symptoms selected from the group        consisting of at least 6 swollen joints, at least 6 tender        joints, and combinations thereof prior to treating.

Embodiment AA1

A pharmaceutical composition for use in treating moderate to severelyactive rheumatoid arthritis in an adult subject, wherein thepharmaceutical composition comprises:

-   -   a) about 7.5 mg per day of        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide        (Compound 1) freebase or a pharmaceutically acceptable salt        thereof, or a crystalline hydrate or crystalline anhydrate of        Compound 1 in an amount sufficient to deliver to the subject        about 7.5 mg per day of Compound 1 freebase equivalent; or    -   b) about 15 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 15 mg per day of        Compound 1 freebase equivalent; or    -   c) about 30 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 30 mg per day of        Compound 1 freebase equivalent; or    -   d) about 45 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 45 mg per day of        Compound 1 freebase equivalent; and    -   wherein the subject has symptoms selected from the group        consisting of at least 6 swollen joints, at least 6 tender        joints, and combinations thereof prior to treating. In certain        aspects of Embodiment AA1, the use comprising administering the        pharmaceutical composition to the subject.

Embodiment AA2

A method of treating moderate to severely active rheumatoid arthritis inan adult subject, the method comprising administering to the subjectabout 7.5 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 7.5 mg per day of Compound 1 freebase equivalent, whereinthe subject has symptoms selected from the group consisting of at least6 swollen joints, at least 6 tender joints, and combinations thereofprior to treating.

Embodiment AA3

The method of Embodiment AA2, comprising administering the crystallinehydrate or crystalline anhydrate of Compound 1 in an amount sufficientto deliver to the subject 7.5 mg of Compound 1 freebase equivalent.

Embodiment AA4

A method of treating moderate to severely active rheumatoid arthritis inan adult subject, the method comprising administering to the subjectabout 15 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 15 mg per day of Compound 1 freebase equivalent, whereinthe subject has symptoms selected from the group consisting of at least6 swollen joints, at least 6 tender joints, and combinations thereofprior to treating.

Embodiment AA5

The method of Embodiment AA4, comprising administering the crystallinehydrate or crystalline anhydrate of Compound 1 in an amount sufficientto deliver to the subject 15 mg of Compound 1 freebase equivalent.

Embodiment AA6

A method of treating moderate to severely active rheumatoid arthritis inan adult subject, the method comprising administering to the subjectabout 30 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg per day of Compound 1 freebase equivalent, whereinthe subject has symptoms selected from the group consisting of at least6 swollen joints, at least 6 tender joints, and combinations thereofprior to treating.

Embodiment AA7

The method of Embodiment AA6, comprising administering the crystallinehydrate or crystalline anhydrate of Compound 1 in an amount sufficientto deliver to the subject 30 mg of Compound 1 freebase equivalent.

Embodiment AA8

A method of treating moderate to severely active rheumatoid arthritis inan adult subject, the method comprising administering to the subjectabout 45 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 45 mg per day of Compound 1 freebase equivalent, whereinthe subject has symptoms selected from the group consisting of at least6 swollen joints, at least 6 tender joints, and combinations thereofprior to treating.

Embodiment AA9

The method of Embodiment AA8, comprising administering the crystallinehydrate or crystalline anhydrate of Compound 1 in an amount sufficientto deliver to the subject 45 mg of Compound 1 freebase equivalent.

Embodiment AA10

The method or composition of any one of Embodiments AA to AA9, whereinsaid symptoms result from the progression of structural damage assessedby radiograph.

Embodiment BB

A method of reducing signs and symptoms of rheumatoid arthritis in anadult subject with moderately to severely active rheumatoid arthritis,the method comprising administering to the subject:

-   -   a) about 7.5 mg per day of        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide        (Compound 1) freebase or a pharmaceutically acceptable salt        thereof, or a crystalline hydrate or crystalline anhydrate of        Compound 1 in an amount sufficient to deliver to the subject        about 7.5 mg of Compound 1 freebase equivalent; or    -   b) about 15 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 15 mg of Compound 1        freebase equivalent; or    -   c) about 30 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 30 mg of Compound 1        freebase equivalent; or    -   d) about 45 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 45 mg of Compound 1        freebase equivalent.

Embodiment BB1

A pharmaceutical composition for reducing signs and symptoms ofrheumatoid arthritis in an adult subject with moderately to severelyactive rheumatoid arthritis, wherein the pharmaceutical compositioncomprises:

-   -   a) about 7.5 mg per day of        (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide        (Compound 1) freebase or a pharmaceutically acceptable salt        thereof, or a crystalline hydrate or crystalline anhydrate of        Compound 1 in an amount sufficient to deliver to the subject        about 7.5 mg of Compound 1 freebase equivalent; or    -   b) about 15 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 15 mg of Compound 1        freebase equivalent; or    -   c) about 30 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 30 mg of Compound 1        freebase equivalent; or    -   d) about 45 mg per day of Compound 1 freebase or a        pharmaceutically acceptable salt thereof, or a crystalline        hydrate or crystalline anhydrate of Compound 1 in an amount        sufficient to deliver to the subject about 45 mg of Compound 1        freebase equivalent.    -   In certain aspects of Embodiment BB1, the use comprising        administering the pharmaceutical composition to the subject.

Embodiment BB2

A method of reducing signs and symptoms of rheumatoid arthritis in anadult subject with moderately to severely active rheumatoid arthritis,the method comprising administering to the subject about 7.5 mg per dayof Compound 1 freebase or a pharmaceutically acceptable salt thereof, ora crystalline hydrate or crystalline anhydrate of Compound 1 in anamount sufficient to deliver to the subject about 7.5 mg of Compound 1freebase equivalent.

Embodiment BB3

The method of Embodiment BB2 wherein the freebase or hydrate oranhydrate is in a once daily extended release formulation.

Embodiment BB4

The method of Embodiment BB2 or BB3, wherein the hydrate is ahemihydrate.

Embodiment BB5

The method of Embodiment BB4, wherein the hemihydrate is FreebaseHydrate Form C.

Embodiment BB6

The method of Embodiment BB2 or BB3, wherein the anhydrate is FreebaseAnhydrate Form D.

Embodiment BB7

The method of any one of Embodiments BB2 to BB6, wherein the crystallinehydrate or the crystalline anhydrate of Compound 1 is administered in anamount sufficient to deliver to the subject 7.5 mg of Compound 1freebase equivalent.

Embodiment BB8

A method of reducing signs and symptoms of rheumatoid arthritis in anadult subject with moderately to severely active rheumatoid arthritis,the method comprising administering to the subject about 15 mg per dayof Compound 1 freebase or a pharmaceutically acceptable salt thereof, ora crystalline hydrate or crystalline anhydrate of Compound 1 in anamount sufficient to deliver to the subject about 15 mg of Compound 1freebase equivalent.

Embodiment BB9

The method of Embodiment BB8, wherein the freebase or hydrate oranhydrate is in a once daily extended release formulation.

Embodiment BB10

The method of Embodiment BB8 or BB9 wherein the hydrate is ahemihydrate.

Embodiment BB11

The method of Embodiment BB10, wherein the hemihydrate is FreebaseHydrate Form C.

Embodiment BB12

The method of Embodiment BB8 or BB9, wherein the anhydrate is FreebaseAnhydrate Form D.

Embodiment BB13

The method of any one of Embodiments BB8 to BB12, wherein thecrystalline hydrate or crystalline anhydrate of Compound 1 isadministered in an amount sufficient to deliver to the subject 15 mg ofCompound 1 freebase equivalent.

Embodiment BB14

A method of reducing signs and symptoms of rheumatoid arthritis in anadult subject with moderately to severely active rheumatoid arthritis,the method comprising administering to the subject about 30 mg per dayof Compound 1 freebase or a pharmaceutically acceptable salt thereof, ora crystalline hydrate or crystalline anhydrate of Compound 1 in anamount sufficient to deliver to the subject about 30 mg of Compound 1freebase equivalent.

Embodiment BB15

The method of Embodiment BB14, wherein the freebase or hydrate oranhydrate is in a once daily extended release formulation.

Embodiment BB16

The method of Embodiment BB14 or BB15, wherein the hydrate is ahemihydrate.

Embodiment BB17

The method of Embodiment BB16 wherein the hemihydrate is FreebaseHydrate Form C.

Embodiment BB18

The method of Embodiment BB14 or BB15, wherein the anhydrate is FreebaseAnhydrate Form D.

Embodiment BB19

The method of any one of Embodiments BB14 to BB17, wherein thecrystalline hydrate or crystalline anhydrate of Compound 1 isadministered in an amount sufficient to deliver to the subject 30 mg ofCompound 1 freebase equivalent.

Embodiment BB20

A method of reducing signs and symptoms of rheumatoid arthritis in anadult subject with moderately to severely active rheumatoid arthritis,the method comprising administering to the subject about 45 mg per dayof Compound 1 freebase or a pharmaceutically acceptable salt thereof, ora crystalline hydrate or crystalline anhydrate of Compound 1 in anamount sufficient to deliver to the subject about 45 mg of Compound 1freebase equivalent.

Embodiment BB21

The method of Embodiment BB20, wherein the freebase or hydrate oranhydrate is in a once daily extended release formulation.

Embodiment BB22

The method of Embodiment BB20 or BB21, wherein the hydrate is ahemihydrate.

Embodiment BB23

The method of Embodiment BB22, wherein the hemihydrate is FreebaseHydrate Form C.

Embodiment BB24

The method of Embodiment BB20 or BB21, wherein the anhydrate is FreebaseAnhydrate Form C.

Embodiment BB25

The method of any one of Embodiments BB20 to BB24 wherein thecrystalline hydrate or crystalline anhydrate of Compound 1 isadministered in an amount sufficient to deliver to the subject 45 mg ofCompound 1 freebase equivalent.

Embodiment BB26

The method or composition of any one of Embodiments BB to BB25, whereinthe method or use further comprises alleviating at least one symptom ofarthritis selected from the group consisting of bone erosion, cartilageerosion, inflammation and vascularity.

Embodiment BB27

The method or composition of Embodiment B26, wherein the method or usefurther comprises alleviating at least one symptom of arthritis selectedfrom the group consisting of joint distortion, swelling, jointdeformation, ankyloses on flexion and severely impaired movement.

Embodiment BB28

The method or composition of any one of Embodiments Y to Y78, Z to Z13,AA to AA10, or BB to BB27, wherein the freebase or hydrate or anhydrateis administered for at least 8 weeks.

Embodiment BB29

The method or composition of Embodiment BB28, wherein the freebase orhydrate is administered for at least 12 weeks.

Embodiment CC

The method or pharmaceutical composition of any one of Embodiments Y toY78, Z to Z13, AA to AA10, or BB to BB29, comprising administering tothe subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mgper day of a crystalline hydrate or a crystalline anhydrate of Compound1.

Embodiment CC1

The method or pharmaceutical composition of any one of Embodiments Y toY78, Z to Z13, AA to AA10, or BB to BB29, wherein the crystallineanhydrate is Freebase Anhydrate Form D.

Embodiment CC2

The method or pharmaceutical composition of any one of Embodiments Y toY78, Z to Z13, AA to AA10, or BB to BB29, wherein the crystallinehydrate of Compound 1 is administered in an amount sufficient to deliverto the subject about 7.5 mg of Compound 1 freebase equivalent.

Embodiment CC2a

The method or pharmaceutical composition of Embodiment CC2, wherein thehydrate is a hemihydrate.

Embodiment CC2b

The method or pharmaceutical composition of Embodiment CC2a, wherein thehydrate is Freebase Hydrate Form C.

Embodiment CC2c

The method or pharmaceutical composition of any one of Embodiments CC2to CC2b, wherein the crystalline hydrate is in a once daily extendedrelease formulation.

Embodiment CC3

The method or pharmaceutical composition of any one of Embodiments Y toY78, Z to Z13, AA to AA10, or BB to BB29, wherein the crystallinehydrate of Compound 1 is administered in an amount sufficient to deliverto the subject about 45 mg of Compound 1 freebase equivalent.

Embodiment CC3a

The method or pharmaceutical composition of Embodiment CC3, wherein thehydrate is a hemihydrate.

Embodiment CC3b

The method or pharmaceutical composition of Embodiment CC3a, wherein thehydrate is Freebase Hydrate Form C.

Embodiment CC3c

The method or pharmaceutical composition of any one of Embodiments CC3to CC3b, wherein the crystalline hydrate is in a once daily extendedrelease formulation.

Embodiment CC4

The method or pharmaceutical composition of any one of Embodiments Y toY78, Z to Z13, AA to AA10, or BB to BB29, wherein the crystallinehydrate of Compound 1 is administered in an amount sufficient to deliverto the subject about 15 mg of Compound 1 freebase equivalent.

Embodiment CC4a

The method or pharmaceutical composition of Embodiment CC4, wherein thehydrate is a hemihydrate.

Embodiment CC4b

The method or pharmaceutical composition of Embodiment CC4a, wherein thehydrate is Freebase Hydrate Form C.

Embodiment CC4c

The method or pharmaceutical composition of any one of Embodiments CC4to CC4b, wherein the crystalline hydrate is in a once daily extendedrelease formulation.

Embodiment CC4d

The method or pharmaceutical composition of any one of Embodiments CC4to CC4c, wherein administration of the crystalline hydrate achieves amean peak plasma concentration (C_(max)) for Compound 1 of from about 25to about 70 ng/mL.

Embodiment CC4e

The method or pharmaceutical composition of any one of Embodiments CC4to CC4d, wherein administration of the crystalline hydrate achieves amean peak plasma concentration (C_(max)) for Compound 1 of from about 25to about 40 ng/mL.

Embodiment CC4f

The method or pharmaceutical composition of any one of Embodiments CC4to CC4e, wherein administration of the hydrate under fasting conditionsachieves a mean C_(max) for Compound 1 of about 26.0 ng/mL.

Embodiment CC4g

The method or pharmaceutical composition of any one of Embodiments CC4to CC4e, wherein administration of the hydrate under fasting conditionsachieves a mean C_(max) for Compound 1 of about 32 ng/mL.

Embodiment CC4h

The method or pharmaceutical composition of any one of Embodiments CC4to CC4g, wherein administration of the hydrate under non-fastingconditions achieves a mean C_(max) for Compound 1 of about 37 ng/mL.

Embodiment CC4i

The method or pharmaceutical composition of any one of Embodiments CC4to CC4g, wherein administration of the hydrate under non-fastingconditions achieves a mean C_(max) for Compound 1 of about 40 ng/mL.

Embodiment CC4j

The method or pharmaceutical composition of any one of Embodiments CC4to CC4i, wherein the difference in the C_(max) for Compound 1 when thehydrate is administered in the fed versus the fasted state is selectedfrom the group consisting of about 30% or less, about 20% or less, andabout 10% or less.

Embodiment CC4k

The method or pharmaceutical composition of any one of Embodiments CC4to CC4j, wherein administration of the crystalline hydrate achieves atime to peak plasma concentration (T_(max)) for Compound 1 of from about1.0 to about 6.0 hours.

Embodiment CC4l

The method or pharmaceutical composition of any one of Embodiments CC4to CC4k, wherein administration of the hydrate under fasting conditionsachieves a T_(max) for Compound 1 of from about 1.0 to about 4.0 hours.

Embodiment CC4m

The method or pharmaceutical composition of any one of Embodiments CC4to CC4k, wherein administration of the hydrate under fasting conditionsachieves a T_(max) for Compound 1 of from about 1.5 to about 6.0 hours.

Embodiment CC4n

The method or pharmaceutical composition of any one of Embodiments CC4to CC4m, wherein administration of the hydrate under fasting conditionsachieves a median T_(max) for Compound 1 of about 3.0 hours.

Embodiment CC4o

The method or pharmaceutical composition of any one of Embodiments CC4to CC4n, wherein administration of the hydrate under non-fastingconditions achieves a T_(max) for Compound 1 of from about 3.0 to about6.0 hours.

Embodiment CC4p

The method or pharmaceutical composition of any one of Embodiments CC4to CC4o, wherein administration of the hydrate under non-fastingconditions achieves a median T_(max) for Compound 1 of about 4.0 hours.

Embodiment CC4q

The method or pharmaceutical composition of any one of Embodiments CC4to CC4p, wherein administration of the crystalline hydrate achieves amean area under the plasma concentration time curve from time 0 toinfinity (AUC_(inf)) for Compound 1 of from about 220 to about 450ng·hours/mL.

Embodiment CC4r

The method or pharmaceutical composition of any one of Embodiments CC4to CC4q, wherein administration of the hydrate under fasting conditionsachieves a mean AUC_(inf) for Compound 1 of about 242 ng·hours/mL.

Embodiment CC4s

The method or pharmaceutical composition of any one of Embodiments CC4to CC4r, wherein administration of the crystalline hydrate achieves aharmonic mean terminal half-life (t_(1/2)) for Compound 1 of from about10.0 to about 14.0 hours.

Embodiment CC4t

The method or pharmaceutical composition of any one of Embodiments CC4to CC4s, wherein administration of the crystalline hydrate achieves aharmonic mean t_(1/2) for Compound 1 of about 12.5 hours.

Embodiment CC4u

The method or pharmaceutical composition of any one of Embodiments CC4to CC4t, wherein administration of the crystalline hydrate achieves amean peak steady-state plasma concentration (C_(max,ss)) for Compound 1of from about 27 to about 55 ng/mL.

Embodiment CC4v

The method or pharmaceutical composition of any one of Embodiments CC4to CC4u, wherein administration of the hydrate under fasting conditionsachieves a mean C_(max,ss) for Compound 1 of about 32 ng/mL.

Embodiment CC4w

The method or pharmaceutical composition of any one of Embodiments CC4to CC4v, wherein administration of the hydrate under non-fastingconditions achieves a mean C_(max,ss) for Compound 1 of about 37 orabout 37 ng/mL.

Embodiment CC4x

The method or pharmaceutical composition of any one of Embodiments CC4to CC4w, wherein administration of the crystalline hydrate achieves atime to peak plasma concentration at steady-state (T_(max,ss)) of fromabout 1.5 to about 6.0 hours.

Embodiment CC4y

The method or pharmaceutical composition of any one of Embodiments CC4to CC4x, wherein administration of the hydrate under fasting conditionsachieves a T_(max,ss) of from about 1.5 to about 4.0 hours.

Embodiment CC4z

The method or pharmaceutical composition of any one of Embodiments CC4to CC4y, wherein administration of the hydrate under fasting conditionsachieves a median T_(max,ss) of about 2.5 hours.

Embodiment CC4aa

The method or pharmaceutical composition of any one of Embodiments CC4to CC4z, wherein administration of the hydrate under non-fastingconditions achieves a T_(max,ss) of from about 2.0 to about 6.0 hours.

Embodiment CC4bb

The method or pharmaceutical composition of any one of Embodiments CC4to CC4aa, wherein administration of the hydrate under non-fastingconditions achieves a median T_(max,ss) of about 4.0 hours.

Embodiment CC4cc

The method or pharmaceutical composition of any one of Embodiments CC4to CC4bb, wherein administration of the crystalline hydrate achieves amean steady-state area under the plasma concentration time curve fromtime 0 to 24 hours (AUC_(24,ss)) for Compound 1 of from about 240 toabout 325 ng·hours/mL.

Embodiment CC4dd

The method or pharmaceutical composition of any one of Embodiments CC4to CC4cc, wherein administration of the hydrate under fasting conditionsachieves a mean AUC_(24,ss) for Compound 1 of about 241 ng·hours/mL.

Embodiment CC4ee

The method or pharmaceutical composition of any one of Embodiments CC4to CC4cc, wherein administration of the hydrate under fasting conditionsachieves a mean AUC_(24,ss) for Compound 1 of about 279 ng·hours/mL.

Embodiment CC4ff

The method or pharmaceutical composition of any one of Embodiments CC4to CC4ee, wherein administration of the hydrate under non-fastingconditions achieves a mean AUC_(24,ss) for Compound 1 of about 317ng·hours/mL.

Embodiment CC4gg

The method or pharmaceutical composition of any one of Embodiments CC4to CC4ee, wherein administration of the hydrate under non-fastingconditions achieves a mean AUC_(24,ss) for Compound 1 of about 322ng·hours/mL.

Embodiment CC4hh

The method or pharmaceutical composition of any one of Embodiments CC4to CC4gg, wherein administration of the crystalline hydrate achieves aharmonic mean steady-state terminal half-life (t_(1/2,ss)) for Compound1 of from about 9.4 to about 10.5 hours.

Embodiment CC4ii

The method or pharmaceutical composition of any one of Embodiments CC4to CC4hh, wherein administration of the crystalline hydrate achieves aharmonic mean t_(1/2,ss) for Compound 1 of about 9.4 hours or about 9.5hours or about 10.3 hours.

Embodiment CC4jj

The method or pharmaceutical composition of any one of Embodiments CC4to CC4ii, wherein administration of the crystalline hydrate achieves amean minimum steady-state plasma concentration (C_(min,ss)) for Compound1 of from about 2.8 to about 3.2 ng/mL.

Embodiment CC4kk

The method or pharmaceutical composition of any one of Embodiments CC4to CC4jj, wherein administration of the crystalline hydrate achieves amean minimum steady-state plasma concentration (C_(min,ss)) for Compound1 of about 2.8 or about 3.0 ng/mL.

Embodiment CC5

The method or pharmaceutical composition of any one of Embodiments Y toY78, Z to Z13, AA to AA10, or BB to BB29, wherein the crystallinehydrate of Compound 1 is administered in an amount sufficient to deliverto the subject about 30 mg of Compound 1 freebase equivalent.

Embodiment CC5a

The method or pharmaceutical composition of Embodiment CC5, wherein thehydrate is a hemihydrate.

Embodiment CC5b

The method or pharmaceutical composition of Embodiment CC5a, wherein thehydrate is Freebase Hydrate Form C.

Embodiment CC5c

The method or pharmaceutical composition of any one of Embodiments CC5to CC5b, wherein the crystalline hydrate is in a once daily extendedrelease formulation.

Embodiment CC5d

The method or pharmaceutical composition of any one of Embodiments CC5to CC5c, wherein administration of the crystalline hydrate achieves amean C_(max) for Compound 1 of from about 55 to about 85 ng/mL.

Embodiment CC5e

The method or pharmaceutical composition of any one of Embodiments CC5to CC5d, wherein administration of the hydrate under fasting conditionsachieves a mean C_(max) for Compound 1 of from about 55 ng/mL to about66 ng/mL.

Embodiment CC5f

The method or pharmaceutical composition of any one of Embodiments CC5to CC5e, wherein administration of the hydrate under fasting conditionsachieves a mean C_(max) for Compound 1 of about 55 ng/mL, or about 56ng/mL, or about 57 ng/mL, or about 59 ng/mL, or about 61 ng/mL, or about64 ng/mL, or about 66 ng/mL.

Embodiment CC5g

The method or pharmaceutical composition of any one of Embodiments CC5to CC5f, wherein administration of the hydrate under non-fastingconditions achieves a mean C_(max) for Compound 1 of from about 74 ng/mLto about 85 ng/mL.

Embodiment CC5h

The method or pharmaceutical composition of any one of Embodiments CC5to CC5g, wherein administration of the hydrate under non-fastingconditions achieves a mean C_(max) for Compound 1 of about 74 ng/mL, orabout 76 ng/mL, or about 77 ng/mL, or about 79 ng/mL, about 82 ng/mL, orabout 84 ng/mL.

Embodiment CC5i

The method or pharmaceutical composition of any one of Embodiments CC5to CC5h, wherein the difference in the C_(max) for Compound 1 when thehydrate is administered in the fed versus the fasted state is selectedfrom the group consisting of about 55% or less, about 53% or less, about20% or less, about 10% or less, from about 3% to about 40%, and fromabout 15% to about 55%.

Embodiment CC5j

The method or pharmaceutical composition of any one of Embodiments CC5to CC5i, wherein administration of the crystalline hydrate achieves aT_(max) for Compound 1 of from about 1.0 to about 8.0 hours.

Embodiment CC5k

The method or pharmaceutical composition of any one of Embodiments CC5to CC5j, wherein administration of the hydrate under fasting conditionsachieves a T_(max) for Compound 1 of from about 1.0 to about 4.0 hours.

Embodiment CC5l

The method or pharmaceutical composition of any one of Embodiments CC5to CC5k, wherein administration of the hydrate under fasting conditionsachieves a median T_(max) for Compound 1 of about 2.0 hours or about 2.5hours, or about 3.0 hours.

Embodiment CC5m

The method or pharmaceutical composition of any one of Embodiments CC5to CC51, wherein administration of the hydrate under non-fastingconditions achieves a T_(max) for Compound 1 of from about 1.5 to about8.0 hours.

Embodiment CC5n

The method or pharmaceutical composition of any one of Embodiments CC5to CC5m, wherein administration of the hydrate under non-fastingconditions achieves a median T_(max) for Compound 1 of about 4.0 hours.

Embodiment CC5o

The method or pharmaceutical composition of any one of Embodiments CC5to CC5n, wherein administration of the crystalline hydrate achieves amean AUC_(inf) for Compound 1 of from about 483 to about 660ng-hours/mL.

Embodiment CC5p

The method or pharmaceutical composition of any one of Embodiments CC5to CC5o, wherein administration of the hydrate under fasting conditionsachieves a mean AUC24_(inf) for Compound 1 of from about 484 to about550 ng·hours/mL.

Embodiment CC5q

The method or pharmaceutical composition of any one of Embodiments CC5to CC5p, wherein administration of the hydrate under fasting conditionsachieves a mean AUC_(inf) for Compound 1 of about 484 ng·hours/mL, orabout 491 ng·hours/mL, or about 495 ng·hours/mL, or about 499ng·hours/mL, or about 513 ng·hours/mL.

Embodiment CC5r

The method or pharmaceutical composition of any one of Embodiments CC5to CC5q, wherein administration of the hydrate under non-fastingconditions achieves a mean AUC_(inf) for Compound 1 of from about 560 toabout 660 ng·hours/mL.

Embodiment CC5B

The method or pharmaceutical composition of any one of Embodiments CC5to CC5r, wherein administration of the hydrate under non-fastingconditions achieves a mean AUC_(inf) for Compound 1 of about 577ng·hours/mL, or about 609 ng·hours/mL, or about 622 ng·hours/mL, orabout 657 ng·hours/mL.

Embodiment CC5t

The method or pharmaceutical composition of any one of Embodiments CC5to CC5s, wherein administration of the crystalline hydrate achieves aharmonic mean t_(1/2) for Compound 1 of from about 9.0 to about 12.0hours.

Embodiment CC5u

The method or pharmaceutical composition of any one of Embodiments CC5to CC5t, wherein administration of the crystalline hydrate achieves amean C_(max,ss) for Compound 1 of from about 65 to about 86 ng/mL.

Embodiment CC5v

The method or pharmaceutical composition of any one of Embodiments CC5to CC5u, wherein administration of the hydrate under fasting conditionsachieves a mean C_(max,ss) for Compound 1 of about 67 ng/mL.

Embodiment CC5w

The method or pharmaceutical composition of any one of Embodiments CC5to CC5u, wherein administration of the hydrate under fasting conditionsachieves a mean C_(max,ss) for Compound 1 of about 68 ng/mL.

Embodiment CC5x

The method or pharmaceutical composition of any one of Embodiments CC5to CC5w, wherein administration of the hydrate under non-fastingconditions achieves a mean C_(max,ss) for Compound 1 of about 80 ng/mL.

Embodiment CC5y

The method or pharmaceutical composition of any one of Embodiments CC5to CC5w, wherein administration of the hydrate under non-fastingconditions achieves a mean C_(max,ss) for Compound 1 of about 84 ng/mL.

Embodiment CC5z

The method or pharmaceutical composition of any one of Embodiments CC5to CC5y, wherein administration of the crystalline hydrate achieves amean AUC_(24,ss) for Compound 1 of from about 485 to about 658ng-hours/mL.

Embodiment CC5aa

The method or pharmaceutical composition of any one of Embodiments CC5to CC5z, wherein administration of the hydrate under fasting conditionsachieves a mean AUC_(24,ss) for Compound 1 of about 525 ng-hours/mL.

Embodiment CC5bb

The method or pharmaceutical composition of any one of Embodiments CC5to CC5aa, wherein administration of the hydrate under non-fastingconditions achieves a mean AUC_(24,ss) for Compound 1 of about 582ng-hours/mL.

Embodiment CC5cc

The method or pharmaceutical composition of any one of Embodiments CC5to CC5aa, wherein administration of the hydrate under non-fastingconditions achieves a mean AUC_(24,ss) for Compound 1 of about 620ng-hours/mL.

Embodiment CC5dd

The method or pharmaceutical composition of any one of Embodiments CC5to CC5cc, wherein administration of the crystalline hydrate achieves aT_(max,ss) of from about 1.5 to about 6.0 hours.

Embodiment CC5ee

The method or pharmaceutical composition of any one of Embodiments CC5to CC5dd, wherein administration of the hydrate under fasting conditionsachieves a T_(max,ss) of from about 2.0 to about 4.0 hours.

Embodiment CC5ff

The method or pharmaceutical composition of any one of Embodiments CC5to CC5ee, wherein administration of the hydrate under fasting conditionsachieves a median T_(max,ss) of about 3.0 hours.

Embodiment CC5gg

The method or pharmaceutical composition of any one of Embodiments CC5to CC5ff, wherein administration of the hydrate under non-fastingconditions achieves a median T_(max,ss) of about 3.5 hours or about 4.0hours.

Embodiment CC5hh

The method or pharmaceutical composition of any one of Embodiments CC5to CC5gg, wherein administration of the crystalline hydrate achieves aharmonic mean t_(1/2,ss) for Compound 1 of from about 10.0 to about 14.5hours.

Embodiment CC5ii

The method or pharmaceutical composition of any one of Embodiments CC5to CC5hh, wherein administration of the crystalline hydrate achieves aharmonic mean t_(1/2,ss) for Compound 1 of about 10.1 hours or about10.4 hours, or about 14.4 hours.

Embodiment CC5jj

The method or pharmaceutical composition of any one of Embodiments CC5to CC5ii, wherein administration of the crystalline hydrate achieves amean C_(min,ss) for Compound 1 of from about 3.5 to about 5.3 ng/mL.

Embodiment CC5kk

The method or pharmaceutical composition of any one of Embodiments CC5to CC5jj, wherein administration of the crystalline hydrate underfasting conditions achieves a mean C_(min,ss) for Compound 1 of about3.8 ng/mL.

Embodiment CC5ll

The method or pharmaceutical composition of any one of Embodiments CC5to CC5jj, wherein administration of the crystalline hydrate undernon-fasting conditions achieves a mean C_(min,ss) for Compound 1 ofabout 4.6 ng/mL or about 5.2 ng/mL.

Embodiment DD

A pharmaceutical composition comprising a crystalline hydrate or acrystalline anhydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(Compound 1) and a pharmaceutically acceptable carrier, wherein thecomposition comprises the crystalline hydrate or the crystallineanhydrate in an amount sufficient to deliver about 7.5 mg of Compound 1freebase equivalent or about 15 mg of Compound 1 freebase equivalent orabout 30 mg of Compound 1 freebase equivalent or about 45 mg of Compound1 freebase equivalent.

Embodiment DD1

A pharmaceutical composition comprising about 7.5 mg, or about 15 mg, orabout 30 mg, or about 45 mg of a crystalline hydrate or a crystallineanhydrate of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(Compound 1), and a pharmaceutically acceptable carrier.

Embodiment DD2

A pharmaceutical composition comprising a crystalline hydrate ofCompound 1 and a pharmaceutically acceptable carrier, wherein thecomposition comprises the crystalline hydrate in an amount sufficient todeliver about 15 mg of Compound 1 freebase equivalent.

Embodiment DD3

A pharmaceutical composition comprising a crystalline hydrate ofCompound 1 and a pharmaceutically acceptable carrier, wherein thecomposition comprises the crystalline hydrate in an amount sufficient todeliver about 30 mg of Compound 1 freebase equivalent.

Embodiment DD4

The composition of any one of Embodiments DD to DD3, wherein the hydrateis Freebase Hydrate Form C.

Embodiment DD5

The composition of any one of Embodiments DD to DD4, wherein the hydrateor the anhydrate is in a once daily extended release formulation.

Embodiment DD6

The composition of Embodiment DD4 or DD5, wherein the compositioncomprises about 15 mg of Freebase Hydrate Form C, and administration ofthe composition to a subject provides:

(a) a mean C_(max) for Compound 1 of from about 25 to about 70 ng/mL;

(b) a T_(max) for Compound 1 of from about 1.0 hours to about 6.0 hours;

(c) a harmonic mean t_(1/2) for Compound 1 of from about 10.0 to about14.0 hours;

(d) a mean AUC_(inf) for Compound 1 of from about 220 to about 450ng-hours/mL;

(e) a mean C_(max,ss) for Compound 1 of from about 27 to about 55 ng/mL;

(f) a mean AUC_(24,ss) for Compound 1 of from about 240 to about 325ng-hours/mL;

(g) a T_(max,ss) for Compound 1 of from about 1.5 to about 6.0 hours;

(h) a mean C_(min,ss) for Compound 1 of from about 2.8 to about 3.2ng/mL;

(i) a harmonic mean t_(1/2,ss) for Compound 1 of from about 9.4 to about10.5 hours;

or any combination thereof.

Embodiment DD7

The composition of Embodiment DD4 or DD5, wherein the compositioncomprises about 30 mg of Freebase Hydrate Form C, and administration ofthe composition to a subject provides:

(a) a mean C_(max) for Compound 1 of from about 55 to about 85 ng/mL;

(b) a T_(max) for Compound 1 of from about 1.0 hours to about 8.0 hours;

(c) a harmonic mean t_(1/2) for Compound 1 of from about 9.0 to about12.0 hours;

(d) a mean AUC_(inf) for Compound 1 of from about 483 to about 660ng-hours/mL;

(e) a mean C_(max,ss) for Compound 1 of from about 65 to about 85 ng/mL;

(f) a mean AUC_(24,ss) for Compound 1 of from about 485 to about 658ng-hours/mL;

(g) a T_(max,ss) for Compound 1 of from about 1.5 to about 6.0 hours;

(h) a mean C_(min,ss) for Compound 1 of from about 3.5 to about 5.3ng/mL;

(i) a harmonic mean t_(1/2,ss) for Compound 1 of from about 10.0 toabout 14.5 hours;

or any combination thereof.

Embodiment DD8

A pharmaceutical composition comprising a crystalline hydrate ofCompound 1 and a pharmaceutically acceptable carrier, wherein thecomposition comprises the crystalline hydrate in an amount sufficient todeliver about 7.5 mg of Compound 1 freebase equivalent.

Embodiment DD9

The composition of Embodiment DD8, wherein the hydrate is FreebaseHydrate Form C.

Embodiment DD10

The composition of Embodiment DD8 or DD9, wherein the hydrate is in aonce daily extended release formulation.

Embodiment DD11

The composition of any one of Embodiments DD8 to DD10, wherein thecomposition comprises the hydrate in an amount sufficient to deliver 7.5mg of Compound 1 freebase equivalent.

Embodiment DD12

A pharmaceutical composition comprising a crystalline hydrate ofCompound 1 and a pharmaceutically acceptable carrier, wherein thecomposition comprises the crystalline hydrate in an amount sufficient todeliver about 45 mg of Compound 1 freebase equivalent.

Embodiment DD13

The composition of Embodiment DD12, wherein the hydrate is FreebaseHydrate Form C.

Embodiment DD14

The composition of Embodiment DD12 or DD13, wherein the hydrate is in aonce daily extended release formulation.

Embodiment DD15

The composition of any one of Embodiments DD12 to DD14, wherein thecomposition comprises the hydrate in an amount sufficient to deliver 45mg of Compound 1 freebase equivalent.

Embodiment EE

A method of treating an adult subject having moderate to severely activerheumatoid arthritis, the method comprising administering to the subjectabout 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg of acrystalline hydrate of Compound 1.

Embodiment EE1

A method of treating structural damage associated with rheumatoidarthritis in an adult subject, the method comprising administering tothe subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mgper day of a crystalline hydrate of Compound 1, such that the structuraldamage in the adult subject is inhibited or lessened.

Embodiment EE2

A method of treating moderate to severely active rheumatoid arthritis inan adult subject, the method comprising administering to the subjectabout 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day ofa crystalline hydrate of Compound 1, wherein the subject has symptomsselected from the group consisting of at least 6 swollen joints, atleast 6 tender joints, and combinations thereof prior to treating.

Embodiment EE3

A method of reducing signs and symptoms of rheumatoid arthritis in anadult subject with moderately to severely active rheumatoid arthritis,the method comprising administering to the subject about 7.5 mg, orabout 15 mg, or about 30 mg, or about 45 mg per day of a crystallinehydrate of Compound 1.

Embodiment EE4

The method of any one of Embodiments EE to EE3, wherein the hydrate is ahemihydrate.

Embodiment EE5

The method of Embodiment EE4, wherein the hydrate is Freebase HydrateForm C.

Embodiment EE6

The method of any one of Embodiments EE to EE5, wherein the hydrate isin a once daily extended release formulation.

Embodiment FF

A pharmaceutical composition comprising about 7.5 mg, or about 15 mg, orabout 30 mg, or about 45 mg of a crystalline hydrate of Compound 1, anda pharmaceutically acceptable carrier.

Embodiment FF1

The composition of Embodiment FF, wherein the hydrate is a hemihydrate.

Embodiment FF2

The composition of Embodiment FF1, wherein the hydrate is FreebaseHydrate Form C.

Embodiment FF3

The composition of any one of Embodiments FF to FF2 wherein the freebaseor the hydrate is in a once daily extended release formulation.

Embodiment GG

An extended release formulation for oral administration comprisingCompound 1 or a pharmaceutically acceptable salt thereof, a hydrophilicpolymer, and a pH modifier, wherein the hydrophilic polymer, in contactwith water, forms a gel layer that provides an environment suitable forCompound 1 and the pH modifier to dissolve.

Embodiment GG1

An extended release formulation for oral administration comprising asolid state form of Compound 1, a hydrophilic polymer, and a pHmodifier, wherein the hydrophilic polymer, in contact with water, formsa gel layer that provides an environment suitable for the solid stateform of Compound 1 and the pH modifier to dissolve.

Embodiment GG1a

The extended release formulation of Embodiment GG1, wherein the solidstate form is a crystalline hydrate.

Embodiment GG1b

The extended release formulation of Embodiment GG1a, wherein thecrystalline hydrate is a hemihydrate.

Embodiment GG1c

The extended release formulation of Embodiment GG1b, wherein thehemihydrate is Freebase Hydrate Form C.

Embodiment GG1d

The extended release formulation of Embodiment GG1a, wherein thecrystalline hydrate is Freebase Hydrate Form B.

Embodiment GG1e

The extended release formulation of Embodiment GG1, wherein the solidstate form is a crystalline anhydrate.

Embodiment GG1f

The extended release formulation of Embodiment GG1e, wherein thecrystalline anhydrate is Freebase Anhydrate Form D.

Embodiment GG2

The extended release formulation of any one of Embodiments GG to GG1f,wherein the environment suitable for Compound 1 or the solid state formto dissolve has a pH equal to or less than 3.8 at 37° C.

Embodiment GG2a

The extended release formulation of any one of Embodiments GG to GG2,wherein the environment suitable for Compound 1 or the solid state formto dissolve has a pH of 1.5 to 3.7.

Embodiment GG3

The extended release formulation of any one of Embodiments GG to GG2a,wherein the environment suitable for Compound 1 or the solid state formto dissolve has a pH of 2.0 to 3.7.

Embodiment GG4

The extended release formulation of any one of Embodiments GG to GG3,wherein the environment suitable for Compound 1 or the solid state formto dissolve has a pH of 2.5 to 3.6.

Embodiment GG5

The extended release formulation of any one of Embodiments GG to GG4,wherein the environment suitable for Compound 1 or the solid state formto dissolve has a pH of 3.0 to 3.6.

Embodiment GG6

The extended release formulation of any one of Embodiments GG to GG5,wherein the environment suitable for Compound 1 or the solid state formto dissolve has a pH of 3.0 to 3.5.

Embodiment GG7

The extended release formulation of any one of Embodiments GG to GG6,wherein the pH modifier is selected from the group consisting oftartaric acid, fumaric acid, citric acid, succinic acid, malic acid, andcombinations thereof.

Embodiment GG8

The extended release formulation of any one of Embodiments GG to GG7,wherein the pH modifier is selected from the group consisting oftartaric acid, fumaric acid, citric acid, succinic acid and combinationsthereof.

Embodiment GG9

The extended release formulation of any one of Embodiments GG to GG8,wherein the pH modifier is selected from the group consisting oftartaric acid, fumaric acid, and combinations thereof.

Embodiment GG10

The extended release formulation of any one of Embodiments GG to GG9,wherein the pH modifier is tartaric acid.

Embodiment GG11

The extended release formulation of any one of Embodiments GG to GG10,wherein the pH modifier is fumaric acid or citric acid.

Embodiment GG12

The extended release formulation of any one of Embodiments GG to GG11,wherein the pH modifier is present in an amount of from about 10 toabout 35 w/w %.

Embodiment GG13

The extended release formulation of any one of Embodiments GG to GG12,wherein the pH modifier is present in an amount of from about 20 toabout 35% w/w.

Embodiment GG14

The extended release formulation of any one of Embodiments GG to GG13,wherein the pH modifier is present in an amount of from about 20 toabout 30% w/w.

Embodiment GG15

The extended release formulation of any one of Embodiments GG to GG14,wherein the pH modifier is present in an amount of from about 20 toabout 25% w/w.

Embodiment GG16

The extended release formulation of any one of Embodiments GG to GG15,wherein the pH modifier is present in an amount of about 30% w/w.

Embodiment GG17

The extended release formulation of any one of Embodiments GG to GG16,wherein the pH modifier is present in an amount of about 20% w/w.

Embodiment GG18

The extended release formulation of any one of Embodiments GG to GG17,wherein the pH modifier is present in an amount of about 10% w/w

Embodiment GG19

The extended release formulation of any one of Embodiments GG to GG18,wherein the hydrophilic polymer is a cellulose derivative with aviscosity between 1000 and 150000 mPa-s.

Embodiment GG20

The extended release formulation of any one of Embodiments GG to GG19,wherein the hydrophilic polymer is selected from the group consisting ofhydroxypropyl methylcellulose, hydroxyethyl cellulose, and mixturesthereof.

Embodiment GG21

The extended release formulation of any one of Embodiments GG to GG20,wherein the hydrophilic polymer is hydroxypropyl methylcellulose.

Embodiment GG22

The extended release formulation of Embodiment GG21, wherein thehydroxypropyl methylcellulose is grade E, F or K.

Embodiment GG22

The extended release formulation of Embodiment GG21, wherein thehydroxypropyl methylcellulose is Hypromellose 2208.

Embodiment HH

A process for preparing a pharmaceutical composition, the processcomprising:

(a) combining(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(Compound 1) or a pharmaceutically acceptable salt thereof, or a solidstate form of Compound 1, and at least a portion of one additionalcomposition component to form a dry granulation mixture;

(b) contacting the dry granulation mixture with a granulation fluid toform a wet granulation mixture;

(c) drying the wet granulation mixture to form a granulated material;

(d) milling the granulated material to form a milled granulatedmaterial;

(e) combining the milled granulation material with any remainingcomposition components; and

(f) compressing the composition to form the pharmaceutical composition

XIII. EXAMPLES Example 1: Preparation of(3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylatedicyclohexylamine salt

(3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylatedicyclohexylamine salt was prepared according to the following reactionscheme:

A. Step A: Preparation of 1-benzyl 3-ethyl4-hydroxy-1H-pyrrole-1,3(2H,5H)-dicarboxylate

To a mixture of carboxybenzyl-glycine ethyl ester (5.5 g, 23.2 mmol) andethyl acrylate (2.3 g, 23.2 mmol) in THF (55 mL) at 0° C. was addedNatOBu (2.2 g, 23.2 mmol) portionwise over 1 hour. The resulting mixturewas warmed to room temperature and stirred overnight. Upon completion,the reaction was quenched with water (30 mL), the pH adjusted to 4.0with concentrated HCl, and the THF removed by distillation. The productwas extracted into DCM (40 mL) and the organic layer washed with water(15 mL). After removal of the DCM the product was crystallized fromdiisopropyl ether/heptane (30 mL/60 mL). The solids were collected byfiltration and washed with heptane (6 mL). The wet material (5.5 gpotency adjusted, 82%) is used directly in the next step.

B. Step B: Preparation of 1-benzyl 3-ethyl4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,3(2H,5H)-dicarboxylate

To a mixture of 1-benzyl 3-ethyl4-hydroxy-1H-pyrrole-1,3(2H,5H)-dicarboxylate (16.2 g dry weight, 55.6mmol) in diisopropyl ether (150 mL) was added at 0° C.trifluoromethanesulfonic anhydride (17.3 g, 61.2 mmol) followed by aslow addition of DIPEA (8.6 g, 66.7 mmol) over 30 min. The resultingmixture was warmed to room temperature and stirred 1 hour. Uponcompletion, the reaction was carefully quenched with 0.5 M HCl (200 mL),additional diisopropyl ether (50 mL) was added and the layers separated.The organic layer was washed twice with water (30 mL) and concentrated.The residue was chased with toluene, taken up in toluene to provide a 30wt % solution (21.7 g potency adjusted, 92%) and used directly in thenext step.

¹H NMR (400 MHz, CDCl₃) δ 7.48-7.28 (m, 5H), 5.20 (s, 2H), 4.60-4.42 (m,4H), 4.42-4.23 (m, 2H), 1.40-1.31 (m, 3H) on a purified sample.

C. Step C: Preparation of 1-benzyl 3-ethyl4-ethyl-1H-pyrrole-1,3(2H,5H)-dicarboxylate

To the toluene solution of triflate from above (21.3 g triflate, 50.3mmol) was added additional toluene (170 mL), water (20 mL), ethylboronic acid (EtB(OH)₂) (5.6 g, 75.4 mmol), potassium carbonate (10.4 g,75.4 mmol) and the resulting mixture was purged with nitrogen.PdCl₂(dppf) (735 mg, 1.0 mmol) was added, the resulting mixture warmedto 85° C. and stirred for 6 hours. Upon completion, the mixture wascooled to room temperature, filtered and the layers separated. Theorganic layer was washed with water, concentrated to approximately 15%of the volume (30 mL) and diluted with heptane (120 mL). The solution ofproduct was treated with activated charcoal, filtered and concentratedto dryness to afford the desired product (13.9 g, 91%)

¹H NMR (400 MHz, CDCl₃) δ 7.50-7.31 (m, 5H), 5.20 (s, 2H), 4.54-4.30 (m,4H), 4.24 (q, J=7.2 Hz, 2H), 2.68 (p, J=7.8 Hz, 2H), 1.36-1.30 (m, 3H),1.22-1.00 (m, 3H).

D. Step D: Preparation of1-((benzyloxy)carbonyl)-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid

To a THF (90 mL) solution of 1-benzyl 3-ethyl4-ethyl-1H-pyrrole-1,3(2H,5H)-dicarboxylate (13.9 g, 46.0 mmol) wasadded 30% aqueous NaOH (61.3 g, 460 mmol). The resulting mixture waswarmed to 50° C. and stirred 7 h. Upon completion, the mixture wascooled to room temperature, additional water (50 mL) was added and thepH adjusted to 9 with concentrated HCl. The THF was removed bydistillation and the aqueous layer washed at 50° C. twice with toluene(2×50 mL). The aqueous layer was cooled to room temperature and the pHadjusted to 4 with concentrated HCl. The resulting slurry of product wasstirred for 2 hours before collecting the solids by filtration. The cakewas washed with water (50 mL) and dried in a vacuum oven. The productwas then dissolved in EtOAc (275 mL) at 75° C., treated with activecharcoal, and filtered. The product crystallized upon cooling to 0° C.,was collected by filtration, washed with EtOAc (2×10 mL), and dried in avacuum oven to afford the desired compound (10.3 g, 83%)

¹H NMR (400 MHz, CDCl₃) δ 7.63-7.33 (m, 5H), 5.20 (s, 2H), 4.51-4.37 (m,4H), 2.78-2.58 (m, 2H), 1.17-1.08 (m, 3H).

E. Step E: Preparation of(3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylatedicyclohexylamine salt

A MeOH (100 mL) solution of1-((benzyloxy)carbonyl)-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid(9.9 g, 36 mmol), TEA (4.2 g, 41.4 mmol) and (S)-segphos Ru(OAc)₂ (29.8mg, 0.04 mmol) was hydrogenated at 580 psi and 80° C. for 2 hours. Uponcompletion, the reaction mixture was cooled to room temperature,filtered and concentrated by distillation. The residue was taken up inEtOAc (50 mL) and water (50 mL) and the pH of the aqueous layer adjustedto 11 with 30% aqueous NaOH. The layers were separated, the pH of theaqueous layer was adjusted to 3 with concentrated HCl, and the productextracted with EtOAc (50 mL). The EtOAc was removed by distillation, theresidue taken up in ACN (75 mL) and filtered. Additional ACN (100 mL)and dicyclohexylamine (6.3 g, 34.6 mmol) was added and the mixtureheated to 80° C. The resulting solution was cooled slowly to roomtemperature and stirred 1 hour. The resulting solids were collected byfiltration, washed with ACN (50 mL) and dried in a vacuum oven toprovide the desired product (14.9 g, 90%, >99% ee).

¹H NMR (400 MHz, CDCl₃) δ 7.47-7.18 (m, 5H), 5.14 (ddd, J=15.5, 12.6,3.7 Hz, 2H), 3.67 (td, J=10.5, 4.8 Hz, 1H), 3.61-3.47 (m, 2H), 3.34(ddd, J=13.4, 10.1, 7.5 Hz, 1H), 3.02-2.77 (m, 3H), 2.33-2.14 (m, 1H),1.96 (t, J=8.0 Hz, 4H), 1.77 (d, J=10.0 Hz, 4H), 1.69-1.53 (m, 3H),1.49-1.30 (m, 5H), 1.29-1.05 (m, 6H), 0.98 (td, J=7.3, 2.5 Hz, 3H).

Example 2: Preparation of ethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate

A degassed mixture of 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (100 g,284 mmol), K₂CO₃ (118 g, 852 mmol), ethyl carbamate (50.6 g, 568 mmol),Palladium (II) acetate (Pd(OAc)₂) (640 mg, 2.8 mmol) and Xantphos (3.3g, 5.7 mmol) in toluene (1 L) was heated to 95° C. and stirredovernight. The resulting mixture was cooled to 50° C. and THF (1 L) wasadded and the solids filtered off rinsing the cake with THF (2 L). Theresulting solution was mixed with a solution of cysteine (50 g) insaturated aqueous sodium bicarbonate (1 L) for two hours. Afterseparating the layers the organic layer was washed with saturatedaqueous sodium bicarbonate (1 L) and brine (500 mL), treated with activecharcoal, filtered and concentrated. The resulting solid was trituratedwith EtOAc (500 mL), the solid collected, washed with EtOAc (100 mL) anddried in a vacuum oven at 50° C. to afford 85 g (83%).

¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 8.86 (s, 1H), 8.22 (d, J=4.0Hz, 1H), 7.99 (d, J=8.5 Hz, 2H), 7.55-7.29 (m, 2H), 6.88 (d, J=4.0 Hz,1H), 4.18 (q, J=7.1 Hz, 2H), 2.35 (s, 3H), 1.26 (t, J=7.1 Hz, 3H).

Example 3: Preparation of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(Compound 1)

Compound 1 was prepared according to the following reaction scheme:

Scheme XV

A. Step A: Preparation of dimethylsulfoxonium2-((3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidin-3-yl)-2-oxo-ethylide

(3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate,(R)-1-(naphthalen-1-yl)ethanamine salt (150 g, 334 mmol) was partitionedbetween MTBE (1.5 L) and 0.5 M H₃PO₄ (750 mL) and stirred 30 min. Afterseparating the layers the organic layer was washed with 0.25 H₃PO₄ (750mL) and saturated aqueous NaCl (500 mL). After concentrating to an oilthe free acid is taken up in THF (250 mL) and stored for later.

To a slurry of CDI (81 g, 501 mmol) in THF (400 mL) was added the THFsolution of(3R,4S)-1-(benzyloxycarbonyl)-4-ethylpyrrolidine-3-carboxylic acid fromabove (93 g, 334 mmol) over 30 minutes. The resulting mixture wasstirred at room temperature for 1 hour. A suspension oftrimethylsulfoxonium chloride (86 g, 668 mmol) and KOtBu (77 g, 685mmol) in THF (1 L) was heated to reflux for 2 hours and then cooled −5°C. The (3S,4R)-benzyl3-ethyl-4-(1H-imidazole-1-carbonyl)pyrrolidine-1-carboxylate solution(109 g, 334 mmol) prepared above was added dropwise over 15 minuteswhile maintaining the internal temperature below −1° C. After theaddition was complete, the solution was quenched with 5% NaCl (1.2 L).The layers were separated and the aqueous layer was extracted with EtOAc(1 L). The combined organic layers were washed with 12% NaCl (600 mL)and concentrated to near dryness. The crude yellow oil was chased withwater (3×400 mL), concentrating to dryness each time, during whichsolids formed. The residue was taken up in water (1.5 L) and heated to70° C. The suspension was allowed to cool to room temperature. Thesolids were collected by filtration, washed with water (2×200 mL), anddried in a vacuum oven. The product was isolated (96.1 g) (82%) as awhite solid.

¹H NMR (400 MHz, DMSO) δ 7.41-7.25 (m, 5H), 5.11-4.93 (m, 2H), 4.76 (s,1H), 3.54-3.23 (m, 9H), 3.15 (dd, J=18.0, 9.6 Hz, 1H), 2.91-2.72 (m,1H), 2.26-2.02 (m, 1H), 1.57-1.39 (m, 1H), 1.20 (tq, J=14.1, 7.3 Hz,1H), 0.88 (td, J=7.4, 2.7 Hz, 3H). MS (ESI+): 352.0 m/e (M+H).

B. Step B: Preparation of (3R,4S)-benzyl3-(2-bromoacetyl)-4-ethylpyrrolidine-1-carboxylate

To a THF (100 mL) solution of dimethylsulfoxonium2-((3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidin-3-yl)-2-oxo-ethylide(10.0 g, 28.5 mmol) and lithium bromide (LiBr) (2.97 g, 34.1 was addedp-toluene sulfonic acid monohydrate (5.95 g, 31.3 mmol). The resultingmixture was warmed to 40° C. and stirred overnight. After cooling toroom temperature, the reaction mixture was diluted with EtOAc (100 mL),washed with water (100 mL), saturated aqueous sodium bicarbonate (100mL) and brine (50 mL). The organic layer was concentrated and usedwithout purification.

¹H NMR (400 MHz, CDCL3) δ 7.41-7.27 (m, 5H), 5.22-5.03 (m, 2H),3.98-3.83 (m, 2H), 3.76-3.65 (m, 1H), 3.65-3.49 (m, 3H), 3.46-3.27 (m,1H), 2.47-2.32 (m, 1H), 1.48-1.21 (m, 2H), 0.99-0.89 (m, 3H). MS (ESI+):353.9 m/e (M+H).

C. Step C: Preparation of (3S,4R)-benzyl3-ethyl-4-(2-((ethoxycarbonyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)pyrrolidine-1-carboxylate

To a DMA (40 mL) suspension of ethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate (8.25 g, 22.9 mmol)(prepared as described in Example 2) cooled to 5° C. was added aN,N-dimethylacetamide (DMA) (20 mL) solution of LiOtBu (1.75 g, 21.9mmol). The resulting solution was stirred 30 minutes and cooled to −10°C. A DMA (20 mL) solution of (3R,4S)-benzyl3-(2-bromoacetyl)-4-ethylpyrrolidine-1-carboxylate from above(approximately 7.1 g, 19.9 mmol) was added over 30 min and stirred at−10° C. for 30 minutes. The resulting mixture was quenched with HOAc(2.3 mL, 40 mmol) and warmed to 25° C. EtOH (40 mL) was added and themixture seeded with the desired product (500 mg). After stirring anadditional 2 hours, a mixture of EtOH (40 mL) and water (20 mL) wasadded over 8 hours. The product was then collected, washed with ethanol(2×40 mL) and dried to afford 10.7 g (88 wt % pure with 12% of thestarting carbamate). A purified sample was prepared by recrystallizingfrom EtOAc.

¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.20 (dd, J=9.0, 4.1 Hz, 1H),8.06-7.86 (m, 2H), 7.51-7.35 (m, 2H), 7.33-7.23 (m, 5H), 6.74 (dd,J=36.1, 4.1 Hz, 1H), 5.02 (d, J=4.1 Hz, 2H), 4.80 (s, 2H), 4.14 (qd,J=7.1, 4.5 Hz, 2H), 3.64-3.34 (m, 4H), 3.21-3.08 (m, 1H), 2.46-2.34 (m,1H), 2.32 (s, 3H), 1.41 (d, J=13.3 Hz, 1H), 1.29-1.08 (m, 4H), 0.86 (td,J=7.3, 4.8 Hz, 3H).

D. Step D: Preparation of (3S,4R)-benzyl3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-1-carboxylate

To a solution of (3S,4R)-benzyl3-ethyl-4-(2-(ethoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)pyrrolidine-1-carboxylate(27.0 g, 42.6 mmol) in ACN (140 mL) was charged pyridine (9.3 mL, 115mmol) and trifluoroacetic anhydride (24.1 mL, 170 mmol) and the mixturewas warmed to 75° C. and stirred for 2 hours. Upon completion, thereaction mixture was cooled to room temperature and concentrated on therotary evaporator. The residue was taken up in 2-methyl tetrahydrofuran(2-MeTHF) (200 mL) and poured into a 20% NaOH solution (200 g) and themixture stirred at 55° C. for 1 hour. Upon completion, the reactionmixture was cooled to room temperature and the layers separated. Theorganic layer was washed with 20% NaOH (100 g) and brine (100 g) and thesolvent switched to EtOH. The EtOH solution was assayed for product(15.2 g, 92%) and carried into the Cbz removal step as a solution.

E. Step E: Preparation of8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazinebis hydrochloride

A mixture of 10% Pd(OH)₂/C (1 g) and (3S,4R)-benzyl3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-1-carboxylate(5.13 g, 13.2 mmol) in EtOH (70 mL) were mixed under hydrogen pressureat 20 psig. The mixture was agitated for 16 hours at 50° C. Uponcompletion, the reaction was cooled to room temperature and filteredthrough a short plug of diatomaceous earth. To this solution was added35% aqueous HCl (2.6 mL, 31.1 mmol) and the mixture concentrated. Theresulting residue was suspended in EtOH (17 mL) and EtOAc (34 mL), andstirred for 1 hour. The crystalline solids were collected, washed withEtOAc/ethanol (2/1, 15 mL) and EtOAc (15 mL) and dried in a vacuum ovento obtain the product (3.63 g, 83%).

¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 10.32-9.91 (m, 2H), 8.91 (s,1H), 8.60 (s, 1H), 7.89 (t, J=3.3 Hz, 1H), 7.29 (dd, J=3.5, 1.9 Hz, 1H),4.58 (q, J=7.4 Hz, 1H), 3.80-3.67 (m, 1H), 3.67-3.55 (m, 2H), 3.20-3.02(m, 1H), 2.75-2.59 (m, 1H), 1.16-1.01 (m, 1H), 1.01-0.87 (m, 1H), 0.65(t, J=7.3 Hz, 3H).

F1. Step F1: Preparation of Compound 1

To a THF (60 mL) slurry of CDI (8.7 g, 53.7 mmol) was added dropwise2,2,2-trifluoroethyl amine (4.52 mL, 57.5 mmol) over 20 minutes whilemaintaining an internal temperature less than 30° C. The resultingsolution was stirred for 1 hour.

To a biphasic mixture of8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazinebis hydrochloride (12.7 g, 38.7 mmol) and potassium phosphate dibasic(K₂HPO₄) (7.4 g, 42.6 mmol) in THF (60 mL) and water (30 mL) was added10% KOH to adjust the pH to 9. The imidazolide from above was added andthe resulting mixture was mixed at 25° C. while maintaining a pH of 9 bythe portionwise addition of 10% KOH for 1 hour. Upon completion, thereaction was quenched with 20% aqueous citric acid (50 mL), stirred for1 hour and the product extracted with EtOAc (2×50 mL). The combinedorganic layers were washed with 15% aqueous KH₂PO₄ (50 mL), saturatedaqueous sodium bicarbonate (50 mL) and brine (25 mL). The solution ofproduct was treated with active charcoal and concentrated bydistillation. The residue was taken up in 2% water in EtOAc (70 mL),seeded and stirred 1 hour. Heptane (35 mL) was added, stirred for 1 hourand the solids collected by filtration. The wet cake was washed with 1%water in EtOAc/heptane (2/1, 2×25 mL) and dried in a vacuum oven toyield the desired product (12.8 g, 87%).

¹H NMR (400 MHz, DMSO-d₆) δ 12.24 (s, 1H), 8.54 (s, 1H), 7.47-7.35 (m,2H), 7.02-6.85 (m, 2H), 4.31 (q, J=6.4 Hz, 1H), 3.91-3.68 (m, 4H), 3.65(dd, J=10.2, 6.9 Hz, 1H), 3.23 (dd, J=10.3, 6.1 Hz, 1H), 2.59-2.48 (m,1H), 1.06 (dtd, J=14.7, 7.4, 4.7 Hz, 1H), 0.84-0.70 (m, 1H), 0.60 (t,J=7.4 Hz, 3H).

F2. Step F2: Alternate Preparation of Compound 1

As an alternative to the Step F1 procedure, Compound 1 was preparedaccording to Step F2.

To a THF (500 mL) slurry of CDI (67.1 g, 414 mmol) was added dropwise2,2,2-trifluoroethylamine (34.6 mL, 441 mmol) over 20 minutes whilemaintaining an internal temperature less than 30° C. The resultingsolution was stirred for 1 hour.

To a biphasic mixture of8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazinebis hydrochloride (91.0 g, 276 mmol) and potassium phosphate dibasic(K₂HPO₄) (48.0 g, 276 mmol) in THF (500 mL) and water (500 mL) was added20% KOH to adjust the pH to 9. The imidazolide from above was added andthe resulting mixture was mixed at 25° C. while maintaining a pH of 9 bythe portionwise addition of 20% KOH for 1 hour. Upon completion, thereaction was quenched with 50% aqueous citric acid (200 g), stirred for1 hour and the product extracted with 2-MeTHF (2×500 mL). The combinedorganic layers were treated with 20% KOH at 50° C. for 30 min and aftercooling to 25° C., the layers were separated, the organic layer waswashed with 15% aqueous KH₂PO₄ (2×500 mL), and brine (250 mL). Thesolution of product was treated with active charcoal.

G. Alternate Process for Crystallization and Isolation of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(Compound 1)

Following the carbon filtration of the solution containing 50 g ofdissolved Compound 1 in Step F2 of Example 3, the solution was distilledto dryness. Two consecutive 250 mL portions of EtOAc were added anddistilled to approximately 100 mL to bring the water content of thesolution to below 1% w/w (as determined by coulometric Karl Fischertitration). This solution was adjusted to a total weight by adding 25%w/w EtOH 200 proof (75 g) and EtOAc (to give 500 g of solution). Thissolution was then treated with a 20 μm Teflon polish filter to removeresidual salts from the reaction work-up. After filtration, the solutionwas again distilled to approximately 100 mL, followed by addition of 2consecutive portions of 250 mL of EtOAc which were each distilled to aminimum volume (achieving a water content of not more than 0.05% w/wwater and not more than 1% w/w EtOH after the final distillation). Thefinal solution was adjusted to approximately 250 mL, and a sample wasanalyzed by HPLC to assay the concentration of Compound 1 (with a targetconcentration of not less than 18% w/w Compound 1).

Crystallization

The distillation product solution (250 g of total solution) wasseparated into two portions: 15% (37.5 g) and 85% (212.5 g) of the totalvolume. The 15% portion was added to the crystallization vessel anddiluted with a premixed solution of EtOAc (353 g) and water (3.95 g) toachieve a final solution of approximately 1.9% w/w of Compound 1 and 1%w/w of water. This solution was allowed to recirculate from thecrystallization vessel via a pump through an IKA wet mill(medium-fine-fine rotor-stator configuration) and returning into the topof the crystallization vessel. The wet mill was set to a rotor tip speedof 9 meters/sec and the crystallization solution was seeded with thedesired crystal form, Freebase Hydrate Form C, of Compound 1. Thiscrystal slurry was allowed to wet mill continuously for not less than 2hours at a recirculation rate giving least 10 turnovers of thecrystallization solution through the wet mill setup. Upon completion,the wet mill tip speed was reduced to 4 meters/sec, and the remaining85% of the Compound 1 product solution was slowly added into thecrystallization vessel over not less than 4 hours. After addition of theentire product solution, the antisolvent, n-heptane, was added slowlyover not less than 4 hours to achieve approximately 30% w/w (260 g) ofn-heptane in the final crystallization liquor (while maintaining a wetmill tip speed of 4 meters/second). Upon completion, wet milling wasdiscontinued, the crystal slurry contents were recirculated into thecrystallization vessel, and the crystal slurry was allowed to mix fornot less than 1 hour.

Isolation and Drying

The crystal slurry was filtered under low pressure (approximately 10psig of nitrogen) while collecting the mother liquor and continued untilthe resulting crystal cake was completely deliquored. A wash solution(69.4% w/w EtOAc, 30% w/w n-heptane, and 0.4% w/w water; 5 volumes ofwash in total, 250 mL) was applied to the wet cake in two portions bydeliquoring the cake completely after each portion. The wet cake waspurged with a stream of nitrogen for not less than 3 hours, and thenheated slowly (˜10° C./hour) to a target temperature of 50° C., not morethan 55° C. and allowed to dry for not less than 12 hours. After 12hours, a sample was taken to analyze the cake for residual ethyl acetateby gas chromatography and water content by Karl Fischer titration. Thefinal dry product was analyzed further for product identity, impurityprofiling, water content and Compound 1 potency.

Example 4: Alternate Process for Preparation of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(Compound 1)

In this example, Steps A-C of the Example 3 process were modified toeliminate certain work up steps and the isolation of the salt, and toimprove purity of the bromomethyl ketone. Specifically, Compound 1 wasprepared according to the following reaction scheme:

A. Step A: Preparation of dimethylsulfoxonium2-((3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidin-3-yl)-2-oxo-ethylide

1-((benzyloxy)carbonyl)-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid(prepared as described in Example 1) (10 g, 36.3 mmol) andRu(OAc)₂—Segphos (0.030 g, 0.036 mmol) were charged to a 300 mL stirredSS Parr reactor, and were transferred to the controlled atmosphereglovebox. A solution of TEA (5.82 mL, 41.8 mmol) in MeOH (60 mL) wasadded, and then the reactor was closed and was removed from the glovebox. The reactor was placed in a reactor station, and was purged firstwith inert gas and then pressurized with hydrogen (200 psig). Themixture was agitated and heated at 80° C. for 4 hours. The reaction wasmonitored by HPLC for conversion.

The reaction mixture was filtered through a polypropylene filter funnelwith diatomaceous earth/polyethylene fritted disc (Chemglass part#OP-6603-12) to remove the catalyst, and MeOH (10 mL) was used as arinse. The combined filtrate obtained was a light amber solution.

The combined filtrate from step 1 was concentrated in vacuo toapproximately 20 mL. The concentrate was diluted with THF (10 g) and wasconcentrated in vacuo to approximately 20 mL. This was repeated fouradditional times. The concentrate was then diluted with THF (40 mL). Tothis solution was added CDI (8.62 g, 53.2 mmol) in portions over 30minutes. The reaction was stirred at room temperature for 1 hour. Thereaction was monitored by HPLC (derivatized with MeOH and DBU) forconversion.

A suspension of trimethylsulfoxonium chloride (9.29 g, 72.2 mmol) andKOtBu (7.18 g, 64.0 mmol) in THF (70 mL) was heated to 45° C. for 1 hourand then cooled −5° C. The (3S,4R)-benzyl3-ethyl-4-(1H-imidazole-1-carbonyl)pyrrolidine-1-carboxylate solution(prepared above) was added dropwise over 1 hour while maintaining theinternal temperature below −1° C. After the addition was complete, thereaction stirred for 1 hour at −5° C. The reaction was monitored by HPLCfor conversion.

The slurry was adjusted to 0° C. and was quenched with water (16 mL).Then the mixture was concentrated in vacuo to approximately 170 mL. Theconcentrate was diluted with water (22 mL) and was concentrated in vacuoto approximately 170 mL. This was repeated five additional times. By thelast concentration, the internal temperature was approximately 45° C.The solution was reduced to 5° C. over 6 hours. During this time theproduct precipitated. The slurry was held at 5° C. for 1 hour, and thenthe product was collected by vacuum filtration. The solid was washedwith water (100 mL) and was dried in a vacuum oven at 45° C. for 24hours. The dimethylsulfoxonium2-((3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidin-3-yl)-2-oxo-ethylide(9.62 g, 27.4 mmol) was isolated in 77% yield.

¹H NMR (400 MHz, DMSO) δ 7.41-7.25 (m, 5H), 5.11-4.93 (m, 2H), 4.76 (s,1H), 3.54-3.23 (m, 9H), 3.15 (dd, J=18.0, 9.6 Hz, 1H), 2.91-2.72 (m,1H), 2.26-2.02 (m, 1H), 1.57-1.39 (m, 1H), 1.20 (tq, J=14.1, 7.3 Hz,1H), 0.88 (td, J=7.4, 2.7 Hz, 3H). MS (ESI+): 352.0 m/e (M+H).

B. Step B: Preparation of (3R,4S)-benzyl3-(2-bromoacetyl)-4-ethylpyrrolidine-1-carboxylate

Dimethylsulfoxonium2-((3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidin-3-yl)-2-oxo-ethylide(10.0 g, 28.5 mmol, 1.0 equivalents), THF (100 mL), and 33% HBr in AcOH(8.37 g, 34.1 mmol, 1.2 equivalents) were charged sequentially andheated to 40° C. The reaction mixture was agitated for 5 hours, cooledto 20° C., and then distilled under vacuum to approximately 65 mL. EtOAc(20 mL) and heptane (50 mL) were charged, and the reaction mixture waswashed with water (5×50 mL). The organic layer was concentrated undervacuum and chased with EtOAc (2×50 mL) concentrating to dryness eachtime. N,N-dimethylacetamide (20 mL) was then charged to provide 30.8 gof a 24.0 wt/wt % solution of (3R,4S)-benzyl3-(2-bromoacetyl)-4-ethylpyrrolidine-1-carboxylate (73% yield). Thesolution was carried forward to the next step.

C. Step C: Preparation of (3S,4R)-benzyl3-ethyl-4-(2-((ethoxycarbonyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)pyrrolidine-1-carboxylate

To a suspension of ethyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate(5.0 g, 13.9 mmol, 1.0 equivalents) and N,N-dimethylacetamide (20 mL) at0° C. was charged a solution of LiOtBu (1.3 g, 16.0 mmol, 1.15equivalents) and N,N-dimethylacetamide (10 mL) over 30 minutes. Afteragitating for 30 minutes, the reaction mixture was cooled to −10° C. Aportion of the bromomethyl ketone solution (23.6 g, 24 wt/wt % in DMA,16.0 mmol, 1.15 equivalents) from Step B above was then added over 1hour. After the addition, the reaction mixture was agitated at −10° C.for 30 minutes, quenched with acetic acid (0.4 mL, 6.9 mmol, 0.5equivalents), and warmed to 20° C. EtOH (40 mL) was then chargedfollowed by seed (25 mg). The resulting slurry was aged at 20° C. for 1hour, heated to 50° C. over 1 hour, and cooled to 20° C. over 3 hours.The heat cycling was performed 5 times total. After the heat cycling wascomplete, water (10 mL) was charged at 50° C. over 2 hours, and theslurry was cooled to 20° C. over 3 hours. The slurry was aged at 20° C.for 2 hours, filtered, and then washed with EtOH (2×25 mL). The isolatedsolids were dried under vacuum at 45° C. to deliver 7.4 g of(3S,4R)-benzyl3-ethyl-4-(2-((ethoxycarbonyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)pyrrolidine-1-carboxylatein 84% yield (99.6% purity).

¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.20 (dd, J=9.0, 4.1 Hz, 1H),8.06-7.86 (m, 2H), 7.51-7.35 (m, 2H), 7.33-7.23 (m, 5H), 6.74 (dd,J=36.1, 4.1 Hz, 1H), 5.02 (d, J=4.1 Hz, 2H), 4.80 (s, 2H), 4.14 (qd,J=7.1, 4.5 Hz, 2H), 3.64-3.34 (m, 4H), 3.21-3.08 (m, 1H), 2.46-2.34 (m,1H), 2.32 (s, 3H), 1.41 (d, J=13.3 Hz, 1H), 1.29-1.08 (m, 4H), 0.86 (td,J=7.3, 4.8 Hz, 3H).

Compound 1 may be prepared from the (3S,4R)-benzyl3-ethyl-4-(2-((ethoxycarbonyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)pyrrolidine-1-carboxylateaccording to the procedure described in Steps D-F of Example 3, andCompound 1 may be isolated and crystallized according to the proceduredescribed in Example 3G.

Example 5: Preparation of Amorphous Freebase

A. Method A: Precipitation From Water

Compound 1 (approximately 300 g) was dissolved in water (10 L) and 50%sodium hydroxide (160 g) was added drop-wise over a two hour period toadjust the pH to greater than 12. Solids formed immediately. The solidswere filtered, washed with two 500 mL aliquots of water, and then driedin a vacuum oven. The solids were equilibrated for a short period oftime at ambient temperature prior to characterization. Conversion toAmorphous Freebase of Compound 1 was confirmed by PXRD analysis.

B. Method B: Dehydration of Freebase Hydrate Form B

A sample of the Freebase Hydrate Form B form of Compound 1 (crystallizedfrom ethanol/water at sub-ambient temperatures as described in Example5, Method C below) was placed in a vacuum oven at 40° C. overnight. Thesolids removed from the vacuum oven were equilibrated for a short timeat 23° C. prior to characterization. Conversion to Amorphous Freebase ofCompound 1 was confirmed by PXRD analysis.

Example 6: Preparation of Freebase Solvate Form A and Freebase HydrateForm B

A. Method A: Freebase Solvate Form A (Isopropyl Acetate/Water Solvate)

A sample of the Amorphous Freebase of Compound 1 (25 mg) was added to avial followed by isopropyl acetate (125 μL) and water (10 μL). Allsolids dissolved at ambient temperature. The solution was placed in afreezer at −16° C. for 4 days. The liquor was decanted and thecrystallized solids were isolated. The isolated crystals were analyzedby PXRD while still wet. Conversion to Freebase Solvate Form A(isopropyl acetate/water solvate) of Compound 1 was confirmed by PXRDanalysis.

B. Method B: Freebase Hydrate Form B from Methanol/Water

A sample of the Amorphous Freebase of Compound 1 (164 mg) and MeOH (621mg) were added to a vial. The components were mixed at ambienttemperature until the solids dissolved. Water (approximately 680 μL) wasadded to the vial and the vial was placed in an ice/sodium chloride bathat approximately −3° C. Crystal seeds comprising Freebase Hydrate Form Bwere added to the vial and the vial was placed in a freezer at −16° C. Asample was pulled from the crystallized suspension and the solids wereimmediately analyzed with PXRD and TGA-MS. Conversion to FreebaseHydrate Form B of Compound 1 was confirmed by PXRD and TGA-MS analysis.

C. Method C: Freebase Hydrate Form B from Ethanol/Water

A sample of the Amorphous Freebase of Compound 1 (4.2 g) was dissolvedin EtOH (15.3g) in a jacketed reactor. Water (23.3 g) was slowly addedto the reactor. The reactor solution was cooled to approximately 2° C. Asmall portion of a seed solution comprising the Freebase Hydrate Form Bwas charged to the reactor. The suspension was mixed at approximately 2°C. for 3 hours and water (36 g) in was charged to the reactor in smallaliquots over several hours while maintaining the suspension at atemperature of approximately 2° C. The crystallized suspension was mixedat approximately 2° C. and the solids were isolated via filtration.Conversion to Freebase Hydrate Form B of Compound 1 was confirmed byPXRD analysis.

The Freebase Solvate Form A and Freebase Hydrate Form B do not readilycrystallize from solution. In general, sub-ambient temperatures andsufficient water activity are needed to crystallize Freebase SolvateForm A and Freebase Hydrate Form B from solution.

Crystalline freebase hydrates and solvates have been isolated fromseveral solvent systems either through primary nucleation (withoutseeding) or through seeding. In addition to crystallization fromisopropyl acetate/water (as described in Method A above), crystallinefreebase hydrates or solvates also have been isolated through primarynucleation (without seeding) from, e.g., n-butylamine/water andethanol/water solvent systems. In addition to crystallization frommethanol/water (as described in Method B above) and ethanol/water (asdescribed in Method C above), crystalline freebase hydrates or solvatesalso have been isolated through seeding from, e.g., acetone/water;acetonitrile/water; ethyl formate/water; methyl acetate/water; ethylacetate/water; methyl ethyl ketone/water; methyl isobutyl ketone/water,methyl isobutyl ketone/methyl tert-butyl ether/water; and isopropylacetate/methyl tert-butyl ether/water solvent systems. The FreebaseSolvate Form A (isopropyl acetate/water solvate) prepared in Method Aabove, the Freebase Hydrate Form B prepared in Methods B and C above,and these other crystalline freebase solvates or hydrates that have beenprepared are isostructural and exhibit similar PXRD patterns. Notably,these crystalline freebase solvates and hydrates are distinguishablefrom and exhibit a different PXRD pattern than Freebase Hydrate Form C(a hemihydrate), which is described below.

The Freebase Solvate Form A and Freebase Hydrate Form B that wereprepared were not stable after isolation at ambient conditions andreadily dehydrated to the Amorphous Freebase.

Example 7: Preparation of Freebase Hydrate Form C

A. Method A: Freebase Hydrate Form C from Ethanol/Water

A sample of the Amorphous Freebase of Compound 1 (2 g) was transferredto a 500 mL beaker equipped with a stirring bar. EtOH (50 g) was addedto the beaker and stirred until all solids dissolved. The solution wastransferred to a 250 mL jacketed flask equipped with a dispersingdevice. The solution was cooled to 6° C. Water (150 g) was added to thesolution and the solution was subjected to high shear for two hoursusing the dispersing device. After solid formation was observed, anadditional amount of water (50 g) was added to the resulting suspension.The suspension was held overnight at ambient temperature. Solids wereisolated and examined on the following day. Conversion to Compound 1Freebase Hydrate Form C was confirmed by PXRD analysis.

B. Method B: Freebase Hydrate Form C from Ethyl Acetate/Heptane/Water

A crude reaction mixture assaying for 11.1 g of Compound 1 was taken upin 2% water in EtOAc (70 g) and seeded with Freebase Hydrate Form C (100mg). The suspension was stirred overnight and heptane (70 g) was added.The solids were collected by filtration, washed with water saturatedEtOAc/heptane (1/1, 100 mL), and dried under vacuum at 50° C. Conversionto Compound 1 Freebase Hydrate Form C was confirmed by PXRD analysis.

As was observed with the Freebase Solvate Form A and the FreebaseHydrate Form B, the Freebase Hydrate Form C also does not readilycrystallize from solution.

Example 8: Preparation of Tartrate Hydrate

Three methods for the preparation of Compound 1 tartrate tetrahydrate(the “Tartrate Hydrate”) are described below. Method A describes aninitial procedure that was used to prepare the tartrate tetrahydrate.Method B describes a modified procedure used to prepare the tartratetetrahydrate at a larger scale. Method C describes a further modifiedprocedure used to prepare the tartrate tetrahydrate. The modifiedprocedure of Method C relative to the procedure of Method B furtherreduces solidification of the filter cake, a potential problem thatpotentially can impact manufacturability and downstream processing.

A. Method A

A sample of the Amorphous Freebase of Compound 1 (28.2 mg) wastransferred to an amber vial. Water (200 μL) and L-tartaric acid (34.5mg (approximately 3 equivalents)) were added to the vial. The suspensionwas vortexed under ambient conditions until all the solids dissolved.The solution in the vial was magnetically stirred at 0° C. The followingday, the solids were isolated from the solution and left at ambienttemperature for a short period of time prior to characterization.Conversion to the Compound 1 Tartrate Hydrate (tetrahydrate) wasconfirmed by PXRD analysis.

B. Method B

Compound 1 (4.6 g) was added to a jacketed reactor followed by theaddition of isopropanol (6.5 mL) and IPAc (7.8 mL). The slurry was mixedat ambient condition until the solids dissolved. In a separate vial,L-tartaric acid (1.96 g) was dissolved in deionized water (3.92 mL). TheL-tartaric acid solution was added to the reactor followed by theaddition of tartrate tetrahydrate seed crystals (28 mg). The suspensionwas mixed for 30 minutes under ambient conditions. IPAc (71 mL) wasadded in small aliquots over 2 hours. The crystallized suspension wascooled to 5° C. and equilibrated at 5° C. overnight. The suspension wasdischarged onto a filter and the filter cake rinsed with 20 mL of watersaturated IPAc. The filtered solids were air-dried for two days.Conversion to the Compound 1 Tartrate Hydrate (tetrahydrate) wasconfirmed by PXRD analysis.

C. Method C

Crystallization: Compound 1 (104 g) was added to a flask together withisopropanol (222.7 g) and IPAc (375.8 g). The components were mixedunder ambient conditions until the solids dissolved. In a separateflask, L-tartaric acid (61.6 g) was dissolved in water (98.3 g). Thecontents of the two flasks were then added to a jacketed reactor.Tartrate tetrahydrate seed crystals (1.55 g) were added to the reactorsolution. The resulting suspension was mixed overnight under ambientconditions. IPAc (2542 g) was charged to the reactor suspension over an8 hour period.

Filtration, Washing and Drying:

Approximately half of the crystallized tartrate suspension was chargedto a jacketed agitated filter dryer. The suspension was cooled insidethe filter dryer to approximately 11° C. The suspension was filteredusing positive pressure until a wet cake was obtained. Water saturatedIPAc (438 g) was charged to the filter dryer and the suspension wasmixed overnight at approximately 11° C. The suspension was filteredusing positive pressure until a wet cake was obtained. Water saturatedMTBE (110 g) was charged to the filter dryer. After 10 minutes, thesuspension was filtered with positive pressure until a wet cake wasobtained. Water saturated MTBE (261 g) was charged to the filter dryerand the suspension was mixed at approximately 11° C. for 3.5 hours. Thesuspension was filtered with agitation using positive pressure until awet cake was obtained. The wet cake was dried with constant agitation ata temperature of approximately 11° C. under humidified nitrogen andpositive pressure for two days. Conversion to the Compound 1 TartrateHydrate (tetrahydrate) was confirmed by PXRD analysis.

Example 9: Preparation of Hydrochloride Solvate Form AA

Initial Preparation:

A sample of the Amorphous Freebase of Compound 1 (23.8 mg), EtOAc (200μL), and concentrated HCl (5 μL) were added to a vial. The viscoussolution was warmed on a hot plate at 50° C. MeOH (20 μL) was added tothe solution and stirring continued. EtOH (10 μL) was added and stirringcontinued at 50° C. The resulting solution was bi-phasic. The vial wasplaced in a bath at 0° C. while mixing with a magnetic stirrercontinued. A white solid was obtained after approximately 1.5 hours.

Larger-Scale Preparation: The above-described procedure was repeated atlarger scale to generate additional solids for characterization. Asample of the Amorphous Freebase of Compound 1 (50.3 mg), EtOAc (500μL), and concentrated HCl (11 μL) were added to a vial. The solution waswarmed on a hot plate and the same viscous phase as observed in theabove-described procedure was obtained. EtOH (40 μL) was added to thesolution and stirring continued. MeOH (40 μL) was added and the vial wasplaced in a bath at 0° C. while mixing with a magnetic stirrercontinued. Once the solution was cooled, a drop of the seed slurry fromthe initial preparation was added. The suspension was mixed for 30minutes in the cooling bath. The vial was placed in a freezer at −16° C.overnight. The solids in the vial were isolated via vacuum filtration.The filtered solids were equilibrated for a short period of time priorto characterization. Conversion to Compound 1 hydrochloride(Hydrochloride Solvate Form AA) was confirmed by PXRD analysis.

Example 10: Preparation of Hydrochloride Solvate Form BB

A sample of the Amorphous Freebase of Compound 1 (76 mg) and THF(approximately 228 μl) were added to a vial. The slurry was sonicateduntil a clear solution was obtained. Concentrated HCl (12 μL) was addedto the clear solution. Some precipitation occurred immediately. The vialwas placed in a freezer at −16° C. for 4 hours. More precipitationoccurred. The solids were isolated from the vial after a few days andequilibrated for a short time at ambient prior to characterization.Conversion to Compound 1 hydrochloride (Hydrochloride Solvate Form BB)was confirmed by PXRD analysis.

Example 11: Preparation of Hydrochloride Solvate Form CC

A sample of the Amorphous Freebase of Compound 1 (50 mg) was dissolvedin 0.2 mL of 50/50 v/v EtOAc/EtOH. Concentrated HCl (40 μL) and 0.8 mLof 50/50 v/v EtOAc/EtOH were added to the solution. EtOAc was slowlydiffused via the gas phase into the product solution (i.e., vapordiffusion procedure). Solids were obtained after approximately threeweeks. The solids were isolated via centrifugation filtration andequilibrated for a short time prior to characterization. Conversion toCompound 1 hydrochloride (Hydrochloride Solvate Form CC) was confirmedby PXRD analysis.

Example 12: Preparation of L-Maleate Form AAA

Compound 1 (78.5 mg), L-maleic acid (32 mg), and water saturated methylisobutyl ketone (630 μL) were add to a vial. A thick slurry formedquickly after the addition of the solvents. Additional methyl isobutylketone was added and the suspension mixed over three days. The isolatedwet solids were equilibrated for a short time prior to characterization.Conversion to the Compound 1 L-Maleate Form AAA was confirmed by PXRDanalysis.

Example 13: Preparation of L-Maleate Form BBB

The L-Maleate Form BBB can be obtained by drying the L-Maleate Form AAAunder vacuum. The L-Maleate Form BBB also can be obtained as describedbelow.

Compound 1 (500 mg), L-maleic acid (150 mg), and water saturated methylisobutyl ketone (4 mL) were add to a vial. The contents of the vial weremixed overnight. Approximately 10 mg of L-Maleate Form BBB crystal seedswere added to the vial. An additional 2 mL of water saturated methylisobutyl ketone was added to the vial. The solids were isolated aftercrystallization and dried at 50° C./75% relative humidity. Conversion tothe Compound 1 L-Maleate Form BBB was confirmed by PXRD analysis.

Example 14: Preparation of Freebase Anhydrate Form D

A sample of the Amorphous Freebase of Compound 1 was dissolved inwater-free EtOAc at a concentration of 19.6% (w/w). An aliquotcomprising approximately 1 mL was transferred to a 4 mL vial equippedwith a magnetic stirrer. The vial was sealed with parafilm and mixed at400 rpm on a magnetic stir plate at around 23° C. for almost 8 weeks.The resulting slurry was filtered and left at ambient conditions for ashort period of time prior to characterization. Conversion to FreebaseAnhydrate Form D was confirmed by PXRD analysis.

Example 15: Microscopy/Crystal Morphology

The solid state forms of Compound 1 were evaluated by microscopy.Samples were examined by microscopic visual examination using apolarizing microscope (model Eclipse E-600 POL, Nikon Corp., GardenCity, N.Y.). A color video camera was used to record digital images(model DXC 390, Fryer Co., Inc., Huntley, Ill.). Images were capturedusing MetaMorph Imaging System (version 4.6R8, Universal ImagingCorporation, Downingtown, Pa.). Observations regarding the crystalmorphology of the samples are reported in Table 15-A below. Those ofskill in the art will recognize that variation in crystal shape and sizemay be observed depending upon the specific crystallization conditionsemployed. The solvation states and PXRD profiles reported in Table 15-Acorrespond to the information presented in the figures and subsequentexamples of this application.

TABLE 15-A Solid Form Solvation/ Nomenclature Species Hydration StateMorphology Amorphous Freebase Anhydrous Blades (when Freebase preparedvia precipitation or dehydration of Freebase Hydrate Form B) FreebaseFreebase Isopropyl Irregular Solvate Form A Acetate/Water SolvateFreebase Freebase Labile Hydrate Blades Hydrate Form B Freebase FreebaseHemihydrate Prisms Hydrate Form C Tartrate Hydrate Tartrate TetrahydrateNeedles Hydrochloride Hydrochloride Solvated, but Not Solvate Formconverts to Determined AA amorphous upon isolation HydrochlorideHydrochloride Solvated, but Not Solvate Form converts to Determined BBamorphous upon isolation Hydrochloride Hydrochloride Solvated, butIrregular Solvate Form converts to CC amorphous upon isolation L-MaleateForm L-Maleate Appears to be Needles AAA either a hydrate or a methylisobutyl ketone/ water solvate L-Maleate Form L-Maleate Not DeterminedNot BBB Determined Freebase Freebase Anhydrous Not Anhydrate FormDetermined D

Example 16: PXRD Analysis

The solid state forms of Compound 1 listed in Table 15-A were analyzedby X-ray powder diffraction (“PXRD”). The PXRD data were collected witha G3000 diffractometer (Inel Corp., Artenay, France) equipped with acurved position sensitive detector and parallel beam optics. Thediffractometer was operated with a copper anode tube (1.5 kW fine focus)at 40 kV and 30 mA. An incident beam germanium monochromator providedmonochromatic Kα1 radiation 2\, =1.540562 Å). The diffractometer wascalibrated using the attenuated direct beam at one-degree intervals.Calibration was checked using a silicon powder line position referencestandard (NIST 640c). Samples were prepared by spreading the samplepowder in a thin layer on an aluminum sample holder and gently levelingwith a glass microscope slide. The instrument was computer controlledusing the Symphonix software (Inel Corp., Artenay, France) and the datawas analyzed using the Jade software (version 6.5, Materials Data, Inc.,Livermore, Calif.). The aluminum sample holder was mounted on therotating sample holder of the G3000 diffractometer and the diffractiondata collected at ambient conditions.

Tables 16-A through 16-J set out the significant parameters of the mainpeaks in terms of 20 values and intensities for the crystalline formsanalyzed. It is known in the art that an X-ray powder diffractionpattern may be obtained which has one or more measurement errorsdepending on measurement conditions (such as equipment, samplepreparation or machine used). In particular, it is generally known thatintensities in an X-ray powder diffraction pattern may fluctuatedepending on measurement conditions and sample preparation. For example,persons skilled in the art of X-ray powder diffraction will realize thatthe relative intensities of peaks may vary according to the orientationof the sample under testing and on the type and setting of theinstrument used. The skilled person also will realize that the positionof reflections can be affected by the precise height at which the samplesits in the diffractometer and the zero calibration of thediffractometer. The surface planarity of the sample also may have aneffect on the results. A person skilled in the art will appreciate thatthe diffraction pattern data presented below is not to be construed asabsolute and any crystalline form that provides a power diffractionpattern substantially identical to those disclosed below fall within thescope of the present disclosure (for further information see Jenkins, R& Snyder, R. L. ‘Introduction to X-Ray Powder Diffractometry’, JohnWiley & Sons, 1996).

The PXRD pattern corresponding to the Amorphous Freebase (viaprecipitation) and the Amorphous Freebase (via dehydration) are shown inFIGS. 2A and 2B, respectively.

The PXRD pattern corresponding to the Freebase Solvate Form A is shownin FIG. 3A. Peak listing of the experimental PXRD pattern with relativeintensities is given in Table 16-A below.

TABLE 16-A PXRD Peak Listing Freebase Solvate Form A (IsopropylAcetate/Water Solvate) PEAK POSITION (°2Θ) RELATIVE INTENSITY 3.1 100.05.4 15.4 6.6 10.7 8.2 8.7 9.4 74.7 10.8 9.2 11.1 6.7 12.1 33.5 13.1 7.415.1 6.4 16.2 11.6 17.0 7.1 19.1 13.3 21.1 20.7 22.3 7.2 22.9 11.9 26.25.8 29.6 4.4

The PXRD pattern corresponding to the Freebase Hydrate Form B is shownin FIG. 3B. Peak listing of the experimental PXRD pattern with relativeintensities is given in Table 16-B below.

TABLE 16-B PXRD Peak Listing Freebase Hydrate Form B PEAK POSITION (°2Θ)RELATIVE INTENSITY 3.1 100.0 6.1 3.4 7.9 4.6 9.3 54.8 10.7 3.1 12.0 27.112.4 6.3 13.0 3.3 13.7 4.3 14.9 7.5 15.6 4.2 16.0 3.5 17.1 3.7 18.8 7.020.8 13.4 22.9 6.6 23.3 4.5 24.0 6.6 24.6 4.2 25.0 12.4 26.0 4.7 26.95.1 28.1 3.3 28.9 2.5 29.8 4.1

The PXRD pattern corresponding to the Freebase Hydrate Form C is shownin FIG. 3C. Peak listing of the experimental PXRD pattern with relativeintensities is given in Table 16-C below.

TABLE 16-C PXRD Peak Listing Freebase Hydrate Form C PEAK POSITION (°2Θ)RELATIVE INTENSITY 7.7 28.8 7.9 41.1 9.6 10.2 10.3 35.0 12.4 9.8 13.472.5 13.9 16.9 15.1 74.6 15.5 93.7 15.9 11.7 17.0 76.1 17.2 46.8 17.821.6 18.1 10.0 18.3 37.2 19.3 33.0 19.7 24.7 20.5 52.4 20.9 54.9 21.27.9 21.7 100.0 21.9 34.6 22.2 21.7 22.6 6.2 23.5 27.2 24.0 5.0 24.4 1824.9 35.1 27.4 9.8 28.2 19.8 29.2 8.2 29.5 13.7 31.5 6.9

The PXRD pattern corresponding to the Tartrate Hydrate is shown in FIG.3D. Peak listing of the experimental PXRD pattern with relativeintensities is given in Table 16-D below. The experimental PXRD patternis shown at the bottom of FIG. 3D and the calculated PXRD pattern isshown at the top of FIG. 3D.

TABLE 16-D PXRD Peak Listing Tartrate Hydrate PEAK POSITION (°2Θ)RELATIVE INTENSITY 3.9 80.3 6.8 24.6 10.4 12.8 11.8 21.6 14.1 100.0 15.763.3 16.1 10.4 17.1 4.5 18.0 22.1 18.4 11.6 18.8 12.4 19.7 5.2 20.0 3.121.2 15.2 21.9 55.9 24.0 11.9 24.8 3.0 25.2 3.6 25.9 32.6 26.7 9.2 27.06.8 27.6 11.5 28.7 6.3 30.4 4.9 30.9 4.9 32.4 4.3 33.4 3.0

The PXRD pattern corresponding to the Hydrochloride Solvate Form AA isshown in FIG. 3E. Peak listing of the experimental PXRD pattern withrelative intensities is given in Table 16-E below.

TABLE 16-E PXRD Peak Listing Hydrochloride Solvate Form AA PEAK POSITION(°2Θ) RELATIVE INTENSITY 4.6 29.3 8.0 31.7 8.4 100.0 11.2 52.1 11.7 16.312.4 62.5 15.6 17.8 16.8 30.1 17.1 44.8 17.7 32.5 18.2 18.7 19.8 63.522.5 30.2 23.0 28.0 24.0 55.8 24.8 39.2 25.3 51.6 27.2 26.8 30.8 10.732.6 15.5

The PXRD pattern corresponding to the Hydrochloride Solvate Form BB isshown in FIG. 3F. Peak listing of the experimental PXRD pattern withrelative intensities is given in Table 16-F below.

TABLE 16-F PXRD Peak Listing Hydrochloride Solvate Form BB PEAK POSITION(°2Θ) RELATIVE INTENSITY 2.48 100.0 2.9 6.4 4.9 60.1 7.2 83.8 7.8 16.48.4 19.8 9.1 15.7 9.5 7.2 10.2 11.6 10.5 26.0 11.0 24.8 12.0 13.7 12.727.6 13.4 11.5 13.7 8.0 14.7 23.6 16.4 13.3 16.9 18.2 17.4 15.1 18.225.4 18.4 17.2 19.2 14.9 19.4 16.2 19.7 15.3 20.3 16.1 20.5 36.1 20.729.4 21.6 9.7 21.8 14.1 22.1 17.8 22.4 11.2 22.8 36.7 23.2 17.1 23.943.0 25.1 12.1 25.7 9.3 26.6 8.8 28.1 8.1 29.9 9.3 30.5 9.7

The PXRD pattern corresponding to the Hydrochloride Solvate Form CC isshown in FIG. 3G. Peak listing of the experimental PXRD pattern withrelative intensities is given in Table 16-G below.

TABLE 16-G PXRD Peak Listing Hydrochloride Solvate Form CC PEAK POSITION(°2Θ) RELATIVE INTENSITY 8.3 100.0 10.8 19.2 11.1 8.4 16.7 19.6 20.2 7.022.9 7.5 23.8 18.4 24.6 11.7 25.1 32.2 27.1 13.7 28.1 5.3 30.6 6.9 32.37.8

The PXRD pattern corresponding to the L-Maleate Form AAA is shown inFIG. 3H. Peak listing of the experimental PXRD pattern with relativeintensities is given in Table 16-H below.

TABLE 16-H PXRD Peak Listing L-Maleate Form AAA PEAK POSITION (°2Θ)RELATIVE INTENSITY 3.2 100.0 9.7 21.6 12.9 78.2 14.1 3.9 14.3 7.6 16.212.8 18.8 13.8 19.1 4.2 19.9 11.4 25.2 5.9 25.7 4.3 26.6 4.8

The PXRD pattern corresponding to the L-Maleate Form BBB is shown inFIG. 3I. Peak listing of the experimental PXRD pattern with relativeintensities is given in Table 16-I below.

TABLE 16-I PXRD Peak Listing L-Maleate Form BBB PEAK POSITION (°2Θ)RELATIVE INTENSITY 3.6 100.0 9.6 14.2 10.8 62.2 12.4 18.4 14.1 14.4 14.58.5 15.7 15.5 16.9 4.1 17.9 14.8 19.0 22.2 20.1 14.9 21.3 2.7 22.5 9.822.9 9.2 25.2 14.1 25.5 9.6 26.0 7.1 26.3 12.4 27.1 3.5 27.7 4.8 28.45.6 28.9 2.9 29.3 4.3 29.6 7.8 32.3 2.2 33.9 3.9

The PXRD pattern corresponding to the Freebase Anhydrate Form D is shownin FIG. 3J. Peak listing of the experimental PXRD pattern with relativeintensities is given in Table 16-J below.

TABLE 16-J PXRD Peak Listing Freebase Anhydrate Form D PEAK POSITION(°2Θ) RELATIVE INTENSITY 4.0 20.6 8.0 29.3 9.7 52.1 11.2 7.5 12.0 9.813.0 1.4 14.2 100.0 14.5 65.7 16.1 3.1 17.2 7.5 18.4 24.3 19.0 23.5 20.343.1 21.4 18.5 23.0 35.7 23.8 18.3 24.7 35.8 25.6 6.0 26.1 14.5 27.411.7 28.2 9.3 28.7 5.2 30.3 6.6 31.1 1.3 31.9 3.8 32.7 1.0 33.3 5.1 34.80.7

Example 17: Unit Cell Parameters

Unit cell parameters were determined for the Freebase Hydrate Form Cbased on a single crystal X-ray diffraction study and are reported belowin Table 17-A. The single crystal X-ray diffraction data were collectedusing a Bruker Apex II diffractometer (Bruker AXS, Madison, Wis.)equipped with an Apex II CCD area detector. The diffractometer wasoperated with a molybdenum anode tube (2.0 kW fine focus) at 50 kV and40 mA. An incident beam silicon monochrometer provided Mo-Kα1monochromatic radiation. The data were collected under a stream of coldnitrogen gas at 100 K using a Kryoflex low temperature device (BrukerAXS, Madison, Wis.). The beam diameter for data collection was 5 mm andthe detector distance was 6 cm. The alignment of the goniometer waschecked using a spherical 2-Dimethylsufuranylidene-1,3-indanedione(YLID) crystal. The instrument was computer controlled using the BIS andApex 2 software programs (Bruker AXS, Madison, Wis.). The data wereanalyzed using Apex 2 software (Version 2011.2-0, Bruker AXS, Madison,Wis.).

TABLE 17-A Unit Cell Parameters Freebase Hydrate Form C Lattice TypeOrthorhombic Space Group P2₁2₁2₁ a (Å) 12.7373 b (Å) 13.0763 c (Å)22.5650 α (°) 90.0 β (°) 90.0 γ (°) 90.0 Volume (Å³) 3758.4 Z 8 Density(g/cm³) 1.376 R-Factor (%) 2.4

Unit cell parameters also were determined for the Tartrate Hydrate basedon data from a PXRD study and are reported below in Table 17-B. The unitcell parameters for the Tartrate Hydrate, however, have not beenconfirmed in a single crystal X-ray diffraction study. The asymmetricunit contains one molecule of Compound 1, one molecule of L-tartaricacid, and 4 molecules of water.

TABLE 17-B Unit Cell Parameters Tartrate Hydrate Lattice Type HexagonalSpace Group P6₃ a (Å) 26.0506 b (Å) 26.0506 c (Å) 7.1652 α (°) 90.0 β(°) 90.0 γ (°) 120.0 Volume (Å³) 4211.09 Z 0

Unit cell parameters also were determined for the Freebase AnhydrateForm D based on a single crystal X-ray diffraction study, performedusing the method as described above for Freebase Hydrate Form C, and arereported below in Table 17-C.

TABLE 17-C Unit Cell Parameters Freebase Anhydrate Form D Lattice TypeOrthorhombic Space Group P2₁2₁2 a (Å) 43.819(8)  b (Å) 8.6147(16) c (Å)9.1957(17) α (°) 90.00 β (°) 90.00 γ (°) 90.00 Volume (Å³) 3471.26(11) Z 8 Density (g/cm³) 1.456 R-Factor (%) 4.94

Example 18: Thermogravimetric Analysis

The solid state forms of Compound 1 listed in Table 15-A were analyzedin a thermogravimetric analysis (“TGA”) study. TGA thermograms werecollected with a Mettler TGA/sDTA 851e (Mettler-Toledo InternationalIncorporated, Scwezenbach, Switzerland) equipped with a TS0801R0 roboticautosampler. The instrument was operated and data evaluated with theStare software (V9.01, Mettler-Toledo International Incorporated,Scwezenbach, Switzerland). The temperature axis was calibrated withindium and aluminum standards. The sample powders were encapsulated inan appropriate pan and scanned at certain rate as specified in TGAthermogram plots. A 50 mL/minute nitrogen purge to the sample chamberwas used. In cases where TGA was run with TA instruments, data werecollected on a thermal balance (Q-500 or Q-5000, TA Instruments, NewCastle, Del.) equipped with a data analyzer (Universal Analysis 2000,version 4.5 Å, TA Instruments, New Castle, Del.). During experiments,the furnace was purged with nitrogen at 60 mL/minute, while the balancechamber was purged at 40 mL/minute. Temperature of the TGA furnace wascalibrated using curie points of aluminum and nickel. Sample size rangedfrom 2 mg to 20 mg, and a heating rate of 10° C./minute was used.

For TGA-MS, the thermogravimetric analysis part was the same as above.The mass of evolved gas was analyzed with PFEIFFER GSD 301 T3 ThermoStar(PFEIFFER Vacuum, Asslar, Germany). The instrument was operated and dataevaluated with Software Quadstar 32-bit (V7.01, Inficon, LI-9496Balzers, Liechtenstein).

For thermogravimetric analyses that were performed on Mettler TGA/sDTA851e (Mettler-Toledo International Incorporated, Scwezenbach,Switzerland), simultaneous Differential Thermal Analysis (sDTA) signalswere also recorded and the data were analyzed with the Stare software(V9.01, Mettler-Toledo International Incorporated, Scwezenbach,Switzerland).

The TGA thermograms corresponding to the Amorphous Freebase (viaprecipitation) and the Amorphous Freebase (via dehydration of FreebaseHydrate Form B) are shown in FIGS. 4A and 4B, respectively.

The TGA thermogram corresponding to the Freebase Solvate Form A is shownin FIG. 4C.

The TGA thermogram corresponding to the Freebase Hydrate Form B is shownin FIG. 4D.

The TGA thermogram corresponding to the Freebase Hydrate Form C is shownin FIG. 4E.

The TGA thermogram corresponding to the Tartrate Hydrate is shown inFIG. 4F.

The TGA thermogram corresponding to the Hydrochloride Solvate Form AA isshown in FIG. 4G.

The TGA thermogram corresponding to the L-Maleate Form BBB is shown inFIG. 4H.

The TGA thermogram corresponding to the Freebase Anhydrate Form D isshown in FIG. 4I.

Amorphous Freebase: TGA indicates that the Amorphous Freebase loses mostof its water at or before 100° C. at a heating rate of 10° C./minute.

Freebase Hydrate Form B: TGA indicates that Freebase Hydrate Form B is alabile hydrate. The exact stoichiometry has not been confirmed. Theavailable data suggest a higher hydrate, possibly 4 to 5 molecules ofwater per molecule of Freebase.

Freebase Hydrate Form C: TGA indicates that Freebase Hydrate Form C is ahemihydrate which is consistent with the single-crystal X-raydiffraction data. In general, TGA at a heating rate of 10° C./minute(ambient relative humidity) shows dehydration of Freebase Hydrate Form Cbetween approximately 120° C. and 160° C. with a weight loss ofapproximately 2.3% to 2.6% between these temperatures.

Tartrate Hydrate: TGA indicates that the Tartrate Hydrate is atetrahydrate. In general, TGA at a heating rate of 10° C./minute(ambient relative humidity) shows dehydration of Tartrate Hydratebetween approximately 25° C. and 160° C. with a weight loss ofapproximately 12% between these temperatures.

Freebase Anhydrate Form D: In general, TGA at a heating rate of 10°C./minute (ambient relative humidity) shows dehydration of FreebaseAnhydrate Form D between about 43° C. and 188° C., with a weight loss ofapproximately 0.5% between these temperatures.

Example 19: Differential Scanning Calorimetry

The solid state forms of Compound 1 listed in Table 15-A were analyzedby differential scanning calorimetry (“DSC”). DSC data were collectedwith a Mettler DSC 823e (Mettler-Toledo International Incorporated,Schwerzenbach, Switzerland) equipped with a TSO801RO roboticautosampler. The instrument was operated and data evaluated with theStare software (V9.01, Mettler-Toledo International Incorporated,Schwerzenbach, Switzerland). The temperature axis was calibrated withindium and aluminum standards. Unless otherwise stated, the sample (2 mgto 5 mg) was encapsulated in a ventilated aluminum pan, pricked justprior to loading into the measurement cell, and heated at a rate of 10°C./minute under a nitrogen gas flow of 50 mL/minute during the study.

The DSC thermogram corresponding to the Amorphous Freebase (viadehydration) is shown in FIG. 5A.

The DSC thermogram corresponding to the Freebase Hydrate Form B is shownin FIG. 5B.

The DSC thermogram corresponding to the Freebase Hydrate Form C is shownin FIG. 5C.

The DSC thermogram corresponding to the Tartrate Hydrate is shown inFIG. 5D.

The DSC thermogram corresponding to the Freebase Anhydrate Form D isshown in FIG. 5E.

Amorphous Freebase: DSC indicates that Amorphous Freebase has a glasstransition onset temperature of about 119° C. with a midpoint of about122° C.

Freebase Hydrate Form B: The DSC thermogram for Freebase Hydrate Form B,at a heating rate of 10° C./minute (ambient relative humidity), showstwo endotherms. The first endotherm relates to loss of water (12.3%) andthe second endotherm relates to both loss of water (5.5%) andincongruent melting.

Freebase Hydrate Form C: The DSC thermogram for Freebase Hydrate Form C,at a heating rate of 10° C./minute (ambient relative humidity), shows anendotherm between approximately 120 and 170° C., with an onsettemperature of 134.7° C. and a peak temperature of 149.9° C.

Tartrate Hydrate: The DSC thermogram for Tartrate Hydrate, at a heatingrate of 10° C./minute (ambient relative humidity), shows an endothermcorresponding to dehydration at approximately 60° C. to 100° C.

Freebase Anhydrate Form D: The DSC thermogram for Freebase AnhydrateForm D, at a heating rate of 10° C./minute (ambient relative humidity),shows an endotherm between about 180° C. and about 220° C., with anonset melting point of about 199.55° C., and a melting enthalpy of 85.4J/g.

As with all thermal analysis, one of skill in the art will appreciatethat the DSC thermogram may change to some extent depending on factorssuch as heating rate, sample particle size, sample purity, samplemoisture content, ambient relative humidity, etc.

Example 20: Moisture Sorption Isotherm

The solid state forms of Compound 1 listed in Table 15-A were analyzedin a moisture vapor isotherm study. Moisture vapor isotherm data werecollected with a DVS Advantage (Surface Measurement Systems Ltd,Alperton, United Kingdom). The sample powder (5 mg to 20 mg) was loadedon a tared pan of the DVS Advantage. The moisture sorption isotherm datawere collected from 30-0-90-0-30% relative humidity in 10% relativehumidity intervals. For each step, the dm/dt criteria was 0.001% over 5minutes, a minimum dm/dt time of 30 minutes, and a maximum dm/dt of 120minutes. Data was collected isothermally at 25° C. with a nitrogen flowrate of 200 cm³/minute. The post DVS sample was kept at approximately30% relative humidity before PXRD analysis.

The moisture sorption isotherm corresponding to the Amorphous Freebase(via dehydration) is shown in FIG. 6A.

The moisture sorption isotherm corresponding to the Freebase HydrateForm C (Hemihydrate) is shown in FIG. 6B.

The moisture sorption isotherm corresponding to the Tartrate Hydrate isshown in FIG. 6C.

The moisture sorption isotherm corresponding to the Freebase AnhydrateForm D is shown in FIG. 6D.

Amorphous Freebase: Moisture sorption isotherm analysis indicates thatthe Amorphous Freebase obtained through dehydration of Freebase HydrateForm B reversibly sorbs up to 13% at 90% relative humidity at 25° C.

Freebase Hydrate Form B: No moisture sorption isotherm could be obtainedfor Freebase Hydrate Form B. The Freebase Hydrate Form B is not stableat ambient conditions and readily dehydrates to the Amorphous Freebase.

Freebase Hydrate Form C: Moisture sorption isotherm analysis indicatesthat the Freebase Hydrate Form C is not hygroscopic.

Tartrate Hydrate: Moisture sorption isotherm analysis indicates that theTartrate Hydrate dehydrates to an amorphous tartrate below 10% relativehumidity at 25° C. If the moisture sorption isotherm analysis isrestricted to a relative humidity range of 10% to 90%, the appearance ofthe moisture sorption isotherm generally will correspond to the moisturesorption shown in FIG. 6C for the Tartrate Hydrate.

Freebase Anhydrate Form D: Moisture sorption isotherm analysis indicatesthat Freebase Anhydrate Form D reversibly sorbs up to 1.8% water at 90%relative humidity at 25° C.

Example 21: Solid State Accelerated Stability Study

The solid state forms of Compound 1 listed in Table 15-A were analyzedin a solid state accelerated stability study. Samples (approximately 1mg to 2 mg) of the solid state form were weighed into glass vials andtested as described below. Chemical stability was acceptable for theAmorphous Freebase, the Freebase Hydrate Form C, and the TartrateHydrate. The L-maleate salt, however, was prone to chemical degradation.

Amorphous Freebase: The Amorphous Freebase exhibited no growth ofdegradation products after storage at 50° C./75% relative humidity (openand closed glass vials) for up to six weeks and after storage at 40°C./75% relative humidity (open and closed glass vials) for up to 24weeks. No material change was observed for any of the attributesevaluated (description, crystal form, assay, impurities and watercontent).

Freebase Hydrate Form C: The Freebase Hydrate Form C surprisinglyexhibited no growth of degradation products under the conditions listedin Table 16-A below (open and closed glass vials):

TABLE 21-A Testing Conditions Storage Condition (Temp ° C./% RH)Packaging Duration Tests 80/75 Open and closed vials 10 Days Description50/75 Open and closed vials 6 Weeks Crystal Form 40/75 Open and closedvials 24 Weeks Assay 30/65 Open and closed vials 24 Weeks Impurities25/60 Double polyethylene 12 Months Water bags, twist tie, in ContentHDPE drumNo material change was observed for any of the attributes evaluated(description, crystal form, assay, impurities and water content).

Tartrate Hydrate: The Tartrate Hydrate exhibited no growth ofdegradation products after storage at 25° C./60% relative humidity (openand closed glass vials) for up to 24 months, after storage at 40° C./75%relative humidity (open and closed glass vials) for least one month, andafter storage at 50° C./75% relative humidity (open and closed glassvials) for up to six weeks. No material change was observed for any ofthe attributes evaluated (description, crystal form, assay, impuritiesand water content).

L-Maleate Form BBB: When stored at 50° C./75% relative humidity (openand closed glass vials), the L-maleate salt degraded to products thatwere not observed for the Freebase Hydrate Form C or the TartrateHydrate.

Example 22: Thermal Degradation Study

The solid state forms of Compound 1 listed in Table 15-A were analyzedin a thermal degradation study. The following pH solutions wereprepared: 0.1N hydrochloric acid (HCl); 50 mM sodium phosphate buffer(pH 7.4, adjusted to 0.155 M ionic strength with sodium chloride) andFasSIF (pH 6.5). For each buffer, a target concentration of about 100μg/mL was prepared by accurately weighing about 1 mg of the solid stateform using a microanalytical balance into a scintillation vial. Water (1mL) was added to dissolve the solid as a stock solution. The stocksolution was diluted 10 times in the various buffers to prepare reactionsolutions. The peak area of the compound in these reaction solutions wasmonitored at 37° C. by HPLC every two hours up to 32 hours total.

Example 23: Solubility Stability

For equilibrium solubility, sufficient solid was added to 3-4 mL liquidmedium in triplicate, such that excess solid remained undissolved. Themixtures were equilibrated for 24-48 hr at 25 rpm on an end-over-endtumbler model 30-1200 (Vankel, Cary, N.C.) in a constant temperaturewater bath. After equilibration, the mixtures were inspected to assurethat the amount of excess solid was sufficient to permitre-characterization. If not, additional solid was added and the mixtureswere again equilibrated for 24-48 hr. The pH of aqueous suspensions wasdetermined after equilibration. The solid phase was separated from theliquid phase by centrifugation at 3300 rpm at equilibration temperatures(i.e., 25° C. or 37° C.). The supernatant was then filtered (13 mmAcrodisc® syringe filter with 0.45μ GHP membrane, Pall® Life Sciences,Ann Arbor, Mich.) to discard the initial 2 mL (to saturate filter) andcapture the last 1 mL for analysis. The filtrate was diluted as neededfor quantification of the material studied by HPLC method (as detailedelsewhere herein). The physical form of the recovered solid wascharacterized by powder X-ray diffraction to examine whether or notphase change had occurred

The results are set forth in Table 23-A.

TABLE 23-A Freebase Hydrate Amorphous Freebase Form C Medium (mg/mL)(mg/mL) pH 1 at 25° C. >3.5 55.3 pH 7.4 at 25° C. 0.68 0.19 FasSIF (pH6.5 at 37° C.) 1.14 0.22 FedSIF (pH 5.0 at 37° C.) 2.13 0.47

Examples 24-27: Extended Release Tablets

The Freebase Hydrate Form C and Amorphous Freebase solid state form ofCompound 1 listed in Table 15-A were formulated into 24 mg extendedrelease tablets according to the formulations set forth in Table 24-A.

TABLE 24-A Extended Release Tablets (no pH modifier) Ex. 24 Ex. 25 Ex.26 (ER1) (ER2) (ER3) Ex. 27 Component Function (mg) (mg) (mg) (mg)Freebase Hydrate Active 24.0 24.0 24.0 — Form C Amorphous FreebaseActive — — — 24.0 Microcrystalline Filler 351.4 303.4 303.4 303.4cellulose (Avicel ® PH 102) HPMC (Methocel ® Release 96.0 96.0 — — K100Premium control LVCRLH) polymer HPMC (Methocel ® Release — 48.0 144.0144.0 K4M Premium CR) control polymer Colloidal silicon Glidant 3.8 3.83.8 3.8 dioxide Magnesium stearate Lubricant 4.8 4.8 4.8 4.8 impalpablepowder Uncoated weight of tablet 480.0 480.0 480.0 480.0

The formulations were prepared by combining and blending the active,microcrystalline cellulose, hydroxypropyl methyl cellulose (HPMC), andcolloidal silicone dioxide. The blend was milled using a Mobil Millfitted with a 610 micron screen. The magnesium stearate was screenedthrough mesh #30 and was added to the bin and blended.

The lubricated granulation was compressed into 480 mg weight tabletsusing a rotary tablet press. The tablets may optionally be coated withany suitable film coating.

The effect of solid state form on the dissolution profile of the tabletswas evaluated. In particular, the dissolution profile of the Example 26(containing Freebase Hydrate Form C as active) and Example 27(containing Amorphous Freebase as active) tablets was evaluated at pH6.8 (representative of the pH in the lower intestine). The dissolutiontest was carried out using the following dissolution parameters andconditions:

-   -   Apparatus: USP Dissolution Apparatus 2 and fraction collector    -   Medium: 900 mL of 50 mM sodium phosphate buffer solution, pH        6.8.    -   Temperature: 37° C.±0.5° C.    -   RPM: 75 RPM±4%    -   Filter: 35 μm PE filter, or equivalent, for automatic sampling    -   Sampling Times: 1, 2, 4, 6, 8, 10, 12, 16, and 20 Hours.        -   Other samples may be taken at other times, as appropriate.    -   Sample Volume: 1.5 mL obtained automatically, without media        replacement.

The medium used for the study was a 0.05 M sodium phosphate buffersolution, pH 6.8±0.05. The medium was prepared using an acid stagemedium (0.1 N hydrochloric acid solution) and a buffer stage concentrate(0.05 M sodium phosphate buffer concentrate solution, prepared bydissolving about 41.4 g of sodium phosphate, monobasic, monohydrate andabout 14.4 g of sodium hydroxide pellets in about 4 L of water, diluteto 6 L with water and mixing well). The medium was prepared by mixing500 mL of the acid stage medium and 400 mL of buffer stage concentratein an appropriate size container or directly in the dissolution vesseland adjusting the pH with 1 N phosphoric acid or 1 N sodium hydroxide,if the pH was not within 6.8±0.05.

For the dissolution test, one tablet each was added to a dissolutionvessel containing 900 mL of the 0.05 M sodium phosphate buffer solutionmaintained at 37° C. The paddles of the dissolution apparatus wereoperated at 75 RPM, with 1.5 mL samples from the dissolution vesselautomatically obtained at the designated time periods. The samplefiltrate was the sample preparation.

For the analysis of the sample, conventional liquid chromatographymethods were utilized, wherein the % of the labelled amount of activereleased (% LA Released) was calculated. The results are set forth inFIG. 7.

As can be seen from FIG. 7, the formulation containing Freebase HydrateForm C (Example 26) as the active showed a slower rate of dissolutionthan the formulation containing Amorphous Freebase (Example 27) as theactive at pH 6.8.

The dissolution profile of formulations comprising Freebase Hydrate FormC as an active was further evaluated at pH 6.8 and in a dual pH system.In particular, the dissolution profile of the Example 24 (ER1), Example25 (ER2), and Example 26 (ER3) tablets at pH 6.8 was carried out asdescribed above. The dissolution profile of the Examples 24-26 tabletswas also carried out in a dual pH system using the following dissolutionparameters and conditions:

Apparatus: USP Dissolution Apparatus 2 and fraction collector

-   -   Medium: Acid Stage: 500 mL of Acid Stage Medium (0.1 N        hydrochloric acid solution)        -   Buffer Stage: 900 mL of 50 mM sodium phosphate buffer            solution, pH 6.8.    -   Temperature: 37° C.±0.5° C.    -   RPM: 75 RPM±4%    -   Filter: 35 μm PE filter, or equivalent, for automatic sampling    -   Sampling Times: Acid Stage: 1 Hour        -   Buffer Stage: 2, 4, 6, 8, 10, 12, 16, and 20 Hours.        -   Other samples may be taken at other times, as appropriate.    -   Sample Volume: Acid: 1.5 mL obtained automatically, without        media replacement.

The acid stage medium is a 0.1 N hydrochloric acid solution. A bufferstage medium for the study was prepared using a buffer stage concentrate(0.05 M sodium phosphate buffer concentrate solution, prepared bydissolving about 41.4 g of sodium phosphate, monobasic, monohydrate andabout 14.4 g of sodium hydroxide pellets in about 4 L of water, diluteto 6 L with water and mixing well). The buffer stage medium of a 0.05 Msodium phosphate buffer solution, pH 6.8±0.05, was prepared by mixing500 mL of the acid stage medium and 400 mL of buffer stage mediumconcentrate in an appropriate size container or directly in thedissolution vessel and adjusting the pH of the buffer stage mediumconcentrate with 1 N phosphoric acid or 1 N sodium hydroxide, if the pHwas not within 6.8±0.05.

For the dissolution test, one tablet each was added to a dissolutionvessel containing 500 mL of a 0.1 N hydrochloric acid solutionmaintained at 37° C. The paddles of the dissolution apparatus wereoperated at 75 RPM for 1 hour, and then a 1.5 mL sample from thedissolution vessel was automatically obtained. After the acid stagesample was obtained, 400 mL of buffer stage medium concentrate wasadded, maintained at 37° C. The dissolution test was continued, with thepaddles remaining at a speed of 75 RPM. The sample filtrate was thesample preparation.

For the analysis of the sample, conventional liquid chromatographymethods were utilized, wherein the % relative standard deviation (RSD)of peak areas was calculated for each set of six standard injections.The results are set forth in FIG. 8.

As can be seen from FIG. 8, after the initial release at the low pH(representative of the pH in the stomach), release of the drug is slowedat the higher pH (representative of the pH in the lower intestine).Therefore, in order to achieve the desired bioavailability, aformulation which allowed pH independent release was required.

Examples 28-35: Extended Release Tablets

The Freebase Hydrate Form C solid state form of Compound 1 listed inTable 15-A was formulated into 15 mg, 24 mg, or 30 mg extended releasetablets according to the formulations set forth in Table 28-A usingdirect compression.

TABLE 28-A Extended Release Tablets (tartaric acid pH modifier) Ex. 33Ex. 28 Ex. 31 Ex. 32 (mg) Ex. 34 Ex. 35 (mg) Ex. 29 Ex. 30 (mg) (mg)(ER4, no (mg) (mg) Component Function (ER7) (mg) (mg) (ER8) (ER4)mannitol) (ER5) (ER6) Freebase Active 15.4^(a)   15.4^(a)   15.4^(a)30.7^(b)   24.6^(c)   24.6^(c)  24.6^(c)  24.6^(c) Hydrate Form CMicrocrystalline Filler 162.4 162.4 162.4 147.1 158.0 210.6 282.6 258.6  cellulose (Avicel ® PH 102) Mannitol Filler 52.6  52.4 — 52.6 52.7 — — — (Pearlitol ® 100 SD) Mannitol Filler — —  52.4 — — — — —(Pearlitol ® 200 SD) Tartaric acid pH 144.0 144.0 144.0 144.0 144.0144.0 96.0 96.0 modifier HPMC Release 96.0 — — 96.0 — — — (Hypromellose2208) control polymer HPMC (Methocel ® Release —  96.0  96.0 —  96.0 96.0 — — K4M Premium CR) control polymer Carbopol ® 71G Release — — — —— 48.0 72.1 control polymer Carbopol ® 971P Release — — — — — 24.0 24.0control polymer Colloidal silicon Glidant 2.4  2.4  2.4 2.4 — — — —dioxide Magnesium stearate Lubricant 7.2  7.2  7.2 7.2  4.8  4.8  4.8 4.8 impalpable powder Uncoated weight of tablet 480.0 479.8 479.8 480.0480.1 480.0 480.0  480.1  Opadry ® II Film coat 14.40 — — 14.40 — — — —Yellow (PVA based) Total weight of tablet 494.39 494.43 — — — —^(a)Provides 15 mg of Compound 1 freebase equivalent. ^(b)Provides 30 mgof Compound 1 freebase equivalent. ^(c)Provides 24 mg of Compound 1freebase equivalent.

The formulations were prepared by first milling the tartaric acidthrough a Fitz mill Model MSA, fitted with a 1512-0027 screen. TheFreebase Hydrate Form C, microcrystalline cellulose, mannitol (whenpresent), milled tartaric acid, release control polymer, and colloidalsilicone dioxide (when present) were combined and blended. The blend wasmilled using a Mobil Mill fitted with a 610 or 1397 micron screen. Themagnesium stearate was screened through mesh #30 and was then added tothe bin and blended. The lubricated granulation was compressed intoabout 480 mg weight tablets using a rotary tablet press.

The Example 28 and 31 tablets were coated using a film coater, whichsprayed a solution containing the Opadry® II Yellow film coat andpurified water until 14.40 mg of coating had been applied to thetablets.

The dissolution profile of the Example 32 (ER4, 24 mg active), Example33 (ER4, no mannitol, 24 mg active), Example 34 (ER5, 24 mg active), andExample 35 (ER6, 24 mg active) tablets was evaluated at pH 1.2, at pH6.8, and in a dual pH system. The pH 6.8 study was performed asdescribed above for Examples 26 and 27. For the dual pH study, an acidstage medium of 0.05 M sodium phosphate solution, pH 3.5±0.05, wasprepared by dissolving about 41.4 g of sodium phosphate, monobasic,monohydrate in about 4 L of water, measuring the pH and addingphosphoric acid, 85%, dropwise as needed to adjust to the target pH. Themixture was diluted to 6 L with water and mixed. A buffer stage mediumfor the study was prepared using a buffer stage concentrate (0.05 Msodium phosphate buffer concentrate solution, prepared by dissolvingabout 41.4 g of sodium phosphate, monobasic, monohydrate and about 14.4g of sodium hydroxide pellets in about 4 L of water, dilute to 6 L withwater and mixing well). The buffer stage medium of a 0.05 M sodiumphosphate buffer solution, pH 6.8±0.05, was prepared by mixing 500 mL ofthe acid stage medium and 400 mL of buffer stage medium concentrate inan appropriate size container or directly in the dissolution vessel andadjusting the pH of the buffer stage medium concentrate with 1 Nphosphoric acid or 1 N sodium hydroxide, if the pH was not within6.8±0.05.

The dissolution test was carried out using the following dissolutionparameters and conditions:

-   -   Apparatus: USP Dissolution Apparatus 2 and fraction collector    -   Medium: Acid Stage: 500 mL of Acid Stage Medium    -   Buffer Stage: 900 mL of 50 mM sodium phosphate buffer solution,        pH 6.8    -   Temperature: 37° C.±0.5° C.    -   RPM: 75 RPM±4%    -   Filter: 35 nm PE filter, or equivalent, for automatic sampling    -   Sampling Times: Acid Stage: 1 Hour        -   Buffer Stage: 2, 4, 6, 8, 10, 12, 16, and 20 Hours.        -   Other samples may be taken at other times, as appropriate.    -   Sample Volume: Acid and Buffer Stage: 1.5 mL obtained        automatically, without media replacement.

For the dissolution test, one tablet each was added to a dissolutionvessel containing 500 mL of the acid stage medium, maintained at 37° C.The paddles of the dissolution apparatus were operated at 75 RPM for 1hour, and then a 1.5 mL sample from the dissolution vessel wasautomatically obtained. After the acid stage sample was obtained, 400 mLof buffer stage medium concentrate was added, and then the mixture wasmaintained at 37° C. The dissolution test was continued, with thepaddles remaining at a speed of 75 RPM. The sample filtrate was thesample preparation.

For the pH 1.2 study, the dissolution test was carried out using thefollowing dissolution parameters and conditions:

-   -   Apparatus: USP Dissolution Apparatus 2 and fraction collector    -   Medium: 500 mL of Acidic Medium, pH 1.2    -   Temperature: 37° C.±0.5° C.    -   RPM: 75 RPM±4%    -   Filter: 35 μm PE filter, or equivalent, for automatic sampling    -   Sampling Times: 1, 2, 4, 6, 8, 10, 12, 16, and 20 Hours.        -   Other samples may be taken at other times, as appropriate.    -   Sample Volume: 1.5 mL obtained automatically, without media        replacement.

For this study, an acidic medium of 0.05 M sodium phosphate solution, pH3.5±0.05, was prepared by dissolving about 41.4 g of sodium phosphate,monobasic, monohydrate in about 4 L of water, measuring the pH andadding phosphoric acid, 85%, dropwise as needed to adjust to the targetpH of 1.2. The mixture was diluted to 6 L with water and mixed.

For the dissolution test, one tablet each was added to a dissolutionvessel containing 500 mL of the acidic medium, maintained at 37° C. Thepaddles of the dissolution apparatus were operated at 75 RPM, with 1.5mL samples from the dissolution vessel automatically obtained at thedesignated time periods. The sample filtrate was the sample preparation.

For the analysis of the sample, conventional liquid chromatographymethods were utilized, wherein the % relative standard deviation (RSD)of peak areas was calculated for each set of six standard injections.The results are set forth in FIG. 9 (Example 32 and 33 tablets), FIG. 10(Example 34 tablet) and FIG. 11 (Example 35 tablet). As can be seen fromFIGS. 9-11, pH independence is achieved in the once daily formulations.

The dissolution profile of the Example 28 (ER7), Example 31 (ER8), andExample 32 (ER4) tablets were evaluated in a dual pH system, asdescribed above. The results are set forth in FIGS. 12 and 13. As can beseen from FIGS. 12 and 13, the formulations provide an extended releaseprofile of 80-100% over a period of about 8-10 hours.

The formulations of Examples 28 and 31-35 all exhibited pH independentrelease of the active ingredient. In contrast, as can be seen from FIG.8, after the initial release at the low pH, release of the active isslowed at the higher pH for the formulations of Examples 24-26. Withoutwishing to be bound to any particular theory, it is believed that theinclusion of tartaric acid as a pH modifier in the Example 28 and 31-35formulations contributed to the pH independent release observed forthese tablets. A comparison of the dissolution profile of the Example 24(no pH modifier), Example 26 (no pH modifier), and Example 32 (tartaricacid pH modifier) tablets in a dual pH system is depicted in FIG. 14.

Example 36: Extended Release Tablet

The Freebase Hydrate Form C solid state form of Compound 1 listed inTable 15-A was formulated into a 7.5 mg extended release tabletaccording to the formulation set forth in Table 36-A.

TABLE 36-A Extended Release Tablets (tartaric acid pH modifier) Ex. 34(mg) Component Function (ER9) Freebase Hydrate Form C* Active 7.678^(a)Microcrystalline cellulose Filler 170.1 (Avicel ® PH 102) Mannitol(Pearlitol ® 100 SD) Filler 52.62 Tartaric acid (crystalline) pHmodifier 144.0 HPMC (Hypromellose 2208) Release control 96.0 polymerColloidal silicon dioxide Glidant 2.4 Magnesium stearate Lubricant 7.2Uncoated weight of tablet 479.998 Opadry ® II Yellow Film coat 14.40Purified water Processing aid n/a Total weight of tablet 494.398^(a)Provides 7.5 mg of Compound 1 freebase equivalent.

The formulation was prepared by first milling the tartaric acid througha Fitz mill Model MSA, fitted with a 1512-0027 screen. The FreebaseHydrate Form C, microcrystalline cellulose, mannitol, milled tartaricacid, release control polymer, and colloidal silicone dioxide werecombined and blended. The blend was milled using a Mobil Mill fittedwith a 610 micron screen. The magnesium stearate was screened throughmesh #30 and was then added to the bin and blended. The lubricatedgranulation was compressed into about 480 mg weight tablets using arotary tablet press.

The tablets were coated using a film coater, which sprayed a solutioncontaining the Opadry® II Yellow film coat and purified water until 14.4mg of coating had been applied to the tablets.

Examples 37-42: Extended Release Tablets

The Freebase Hydrate Form C solid state form of Compound 1 listed inTable 15-A was formulated into 15 mg or 30 mg extended release tabletsaccording to the formulations set forth in Table 37-A. The tablets wereprepared using a wet granulation process, and were compressed intotablets having a core weight of about 480 mg.

TABLE 37-A Extended Release Tablets (tartaric acid pH modifier) Ex. 37Ex. 38 Ex. 39 Ex. 40 Ex. 41 Ex. 42 (mg) (mg) (mg) (mg) (mg) (mg)Component Function (ER10) (ER11) (ER12) (ER13) (ER14) (ER15) Tablet Core(Intragranular) Freebase Hydrate Form C Active 30.7^(a) 30.7^(a)30.7^(a) 15.4^(b) 15.4^(b) 15.4^(b) Microcrystalline cellulose Filler79.9 79.9 79.9 40.0 40.0 40.0 (Avicel ® PH 101) HPMC (HypromelloseRelease control 9.5 9.5 9.5 4.8 4.8 4.8 2208) polymer Tablet Core(Extragranular) Microcrystalline cellulose Filler 67.2 67.2 67.2 122.5122.5 122.5 (Avicel ® PH 102) Mannitol Filler 52.6 100.6 148.6 52.6100.6 148.6 Tartaric acid (crystalline) pH modifier 144.0 96.0 48.0144.0 96.0 48.0 HPMC (Hypromellose Release control 86.5 86.5 86.5 91.291.2 91.2 2208) polymer Colloidal silicon Glidant 2.4 2.4 2.4 2.4 2.42.4 dioxide/silica Magnesium stearate Lubricant 7.2 7.2 7.2 7.2 7.2 7.2Uncoated weight of tablet 480.0 480.0 480.0 480.1 480.1 480.1 Opadry ®II Yellow^(c) Film coat 14.4 14.4 14.4 14.4 14.4 14.4 Total weight oftablet 494.4 494.4 494.4 494.5 494.5 494.5 ^(a)Provides 30 mg ofCompound 1 freebase equivalent. ^(b)Provides 15 mg of Compound 1freebase equivalent. ^(c)Film coat weight is approximate.

The formulation was prepared by first milling the tartaric acid througha Fitz mill Model MSA, fitted with a 1512-0027 screen. The intragranularportion of the hydroxypropylmethyl cellulose release control polymer,the Freebase Hydrate Form C, and intragranular portion of themicrocrystalline cellulose filler were added to a granulator, and mixed.Water was sprayed to granulate. The granulated material was then driedand milled using a comill fitted with a 610 micron screen. The milledgranulation was then added to the extragranular tablet components otherthan magnesium stearate, and sieved using a comill fitted with a 1397micron screen, followed by blending. The magnesium stearate was thenadded to the bin and blended. The lubricated granulation was compressedinto about 480 mg weight tablets using a rotary tablet press.

The tablets were coated using a film coater, which sprayed a solutioncontaining the Opadry® II Yellow film coat and purified water until 14.4mg of coating had been applied to the tablets.

Example 43: Evaluation of the Effect of Organic Acids on DissolutionProfile of Extended Release Tablets

In this example, the effect of various organic acid pH modifiers (e.g.,tartaric acid, citric acid, succinic acid, and fumaric acid) on therelease rate of Freebase Hydrate Form C from 24 mg once-daily extendedrelease (ER) tablets was evaluated. Freebase Hydrate Form C wasformulated into 24 mg extended release tablets according to theformulations set forth in Table 43-A.

TABLE 43-A Extended Release Tablets Tartaric acid Citric acid Succinicacid Fumaric acid Component Function A B C D E F G H Freebase Active24.6 24.6 24.6 24.6 24.6 24.6 24.6 24.6 Hydrate Form C MicrocrystallineFiller 306.6 306.6 306.6 306.6 306.6 306.6 306.6 306.6 cellulose(Avicel ® PH 102) HPMC Release 96.0 — 96.0 — 96.0 — 96.0 — (Methocel ®control K4M) polymer Carbopol ® 71G Release — 96.0 — 96.0 — 96.0 — 96.0control polymer Organic acid pH 48.0 48.0 48.0 48.0 48.0 48.0 48.0 48.0modifier Magnesium Lubricant 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 stearateTotal 480.0 480.0 480.0 480.0 480.0 480.0 480.0 480.0

The formulations were prepared by first milling the organic acid througha Fitz mill Model MSA, fitted with a 1512-0027 screen. The active,microcrystalline cellulose, milled organic acid, and release controlpolymer, were combined and blended. The blend was milled using a MobilMill fitted with a 610 micron screen. The magnesium stearate wasscreened through mesh #30 and was added to the bin and blended. Thelubricated granulation was compressed into 480 mg weight tablets using arotary tablet press.

The effect of the organic acids on the dissolution profile of thetablets was evaluated at pH 1.2 and pH 6.8. The dissolution tests werecarried out using the dissolution parameters and conditions as describedabove in Examples 26 and 27 and 32-35. For analysis of the sample,conventional liquid chromatography methods were utilized, wherein the %of the labelled amount of active released (% LA Released) wascalculated. The results are set forth in FIGS. 15A-15H.

As can be seen from these results, organic acids improved dissolutionrate at high pH, with tartaric acid showing the best improvement. Theformulations comprising the control release polymer Carbopol® withtartaric acid provided near linear release at pH 6.8.

Example 44: Gel pH Measurements for Tablets with Different Amounts ofTartaric Acid

To measure the pH of the environment created when Compound 1 reacts withHPMC, the following experiment was performed.

The Freebase Hydrate Form C solid state form of Compound 1 wasformulated into 30 mg extended release tablets according to theformulations set forth in Table 44-A. The tablets were prepared using awet granulation process, as described in Examples 37-42.

Dissolution media of 0.01 N HCl (pH 2) and 113 mM sodium phosphatebuffer (pH 6.8) was prepared at 37° C. One tablet was added to 500 mL of0.01 N HCl media and stirred at 75 rpm at 37° C. for one hour in aVankel VK 7010 dissolution bath. Then 400 mL of sodium phosphate bufferwas added. The solution was stirred an additional three hours. Thetablet was removed, rinsed with water and dried using laboratorytissues. The gel that formed on the tablet was separated from the drycore for pH measurement. This procedure was repeated three times foreach formulation. The pH of the gel formed on the tablets is set forthin Table 44-B. The pH results are plotted in FIG. 31.

TABLE 44-A Formulations Formula- Formula- Formula- Formula- Formula-tion 1 tion 2 tion 3 tion 4 tion 5 Component mg/tab mg/tab mg/tab mg/tabmg/tab Intragranular Freebase 30.71 30.71 30.71 30.71 30.71 Hydrate FormC HPMC 3.920 3.920 3.920 3.920 3.920 (Methocel ® K4M) Micro- 30.71 30.7130.71 30.71 30.71 crystalline cellulose (Avicel ® PH102) extragranularMicro- 116.4 164.4 188.4 212.4 260.4 crystalline cellulose (Avicel ®PH102) Tartaric Acid 144.0 96.00 72.00 48.00 0.00 (milled) Mannitol52.62 52.62 52.62 52.62 52.62 (Pearlitol ® 100SD) HPMC 92.08 92.08 92.0892.08 92.08 (Methocel ® K4M) Colloidal 2.400 2.400 2.400 2.400 2.400silicon dioxide Magnesium 7.200 7.200 7.200 7.200 7.200 Stearate Total480.04 480.04 480.04 480.04 480.04

TABLE 44-B pH Results % Tartaric Formulation Acid 1^(st) tablet 2^(nd)tablet 3^(rd) tablet Average 1 30 2.63 2.68 2.81 2.71 2 20 3.17 3.093.23 3.16 3 15 3.42 3.94 3.65 3.67 4 10 3.88 3.67 3.77 3.77 5 0 6.266.21 6.55 6.34

Example 45: Evaluation of the In Vivo Pharmacokinetic Profile of 15 mgExtended Release Tablets (Fasting)

The pharmacokinetic profile of the 15 mg once-daily extended release(ER) tablets prepared in Example 28 was evaluated, and compared to thatof a 12 mg immediate-release (IR) capsule comprising Tartrate Hydrate asthe active.

Healthy human subjects (n=11) were administered a single dose of the 12mg IR capsule (Regimen A) and the 15 mg ER (once-daily) tablet fromExample 28 (Regimen B) under fasting conditions in a randomized,two-period, cross-over study design. Subjects were administered RegimenA in the first study period and Regimen B in the second study period, oradministered Regimen B in the first study period and Regimen A in thesecond study period. Serial blood samples were collected from eachsubject prior to dosing and for 72 hours after dosing in each studyperiod. Upon collection, the samples were promptly placed in an icebath, and within 2 hours after sample collection they were centrifugedat about 4° C. The resulting plasma samples were placed in cleanpolypropylene-tubes and stored in a freezer until analysis. The plasmasamples were assayed for Compound 1 using appropriate liquidchromatography mass spectrometry procedures. Pharmacokinetic parameterswere estimated using non-compartmental methods, and summary statisticswere computed for each parameter by regimen.

The results are summarized in Table 45-A. The mean concentration ofCompound 1 at each time point using linear (FIG. 16A) and semi-log (FIG.16B) scales for each of the two regimens is set forth in FIGS. 16A and16B.

TABLE 45-A Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of 15 mg ER Tablet and 12 mg IR CapsuleFormulations Under Fasting Conditions Regimen A Regimen B PK ParameterUnits (IR Capsule, 12 mg) (ER Tablet, 15 mg) C_(max) ng/mL 64.6 (16)26.0 (37) T_(max) ^(a) hours 1.0 (0.5-1.5) 3.0 (1.0-4.0) t_(1/2) ^(b)hours 9.2 (119) 12.5 (90) AUC_(t) ng · h/mL 231 (15) 227 (26) AUC_(inf)ng · h/mL 234 (15) 242 (26) ^(a)Median (minimum, maximum) ^(b)Harmonicmean (pseudo-% CV) ^(c)Data in parentheses is coefficient of variance ofthe PK parameter (% CV), unless otherwise indicated.

As can be seen from this data, the 15 mg ER tablet provided a lowerC_(max) and comparable AUC to the 12 mg IR capsule under fastingconditions.

The relative bioavailability for a single dose of the once-daily (ER)tablet formulation (Regimen B) relative to the IR capsule formulation(Regimen A) was also determined based on analysis of the naturallogarithms of C_(max) and AUC. The results are summarized in Table 45-Bbelow.

TABLE 45-B Relative Bioavailability and 90% Confidence Intervals forBioequivalence Assessment Relative Bioavailability 90% Confidence PKParameter Point Estimate Interval C_(max) 0.373 0.312-0.446 AUC_(t)0.939 0.869-1.013 AUC_(inf) 0.992 0.909-1.082

For Regimen B versus Regimen A, the point estimates for the ratios ofAUC_(t) and AUC_(inf) were near unity, and the 90% confidence intervalswere within the 0.86-1.09 range.

Example 46: Evaluation of the In Vivo Pharmacokinetic Profile of 30 mgExtended Release Tablets (Fasting)

The pharmacokinetic profile of the 30 mg once daily extended release(ER) tablets prepared in Example 31 was evaluated, and compared to thatof a 24 mg dose of an immediate release (IR) capsule comprising TartrateHydrate as the active.

Healthy human subjects (n=12) were administered a single 24 mg dose (two12 mg IR capsules) (Regimen C) and the 30 mg ER (once daily) tablet fromExample 31 (Regimen D) under fasting conditions in a randomized,two-period, cross-over study design. Half the subjects were administeredRegimen C in the first study period and Regimen D in the second studyperiod, while the other half were administered Regimen D in the firststudy period and Regimen C in the second study period. Serial bloodsamples were collected from each subject prior to dosing and for 72hours after dosing in each study period. Upon collection, the sampleswere promptly placed in an ice bath, and within 2 hours after samplecollection they were centrifuged at about 4° C. The resulting plasmasamples were placed in clean polypropylene-tubes and stored in a freezeruntil analysis. The plasma samples were assayed for Compound 1 usingappropriate liquid chromatography mass spectrometry procedures.Pharmacokinetic parameters were estimated using non-compartmentalmethods, and summary statistics were computed for each parameter byregimen.

The results are summarized in Table 46-A. The mean concentration ofCompound 1 at each time point using linear (FIG. 17A) and semi-log (FIG.17B) scales for each of the two regimens is set forth in FIGS. 17A and17B.

TABLE 46-A Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of 30 mg ER Tablet and 24 mg Dose (2 × 12 mg)IR Capsule Formulations Under Fasting Conditions Regimen C Regimen D PKParameter Units (IR Capsules, 24 mg) (ER Tablet, 30 mg) C_(max) ng/mL176 (37) 63.7 (33) T_(max) ^(a) hours 0.5 (0.5-1.5) 2.0 (1.5-4.0)t_(1/2) ^(b) hours 9.9 (52) 10.8 (67) AUC_(t) ng · h/mL 520 (25) 477(27) AUC_(inf) ng · h/mL 524 (25) 491 (27) ^(a)Median (minimum-maximum)^(b)Harmonic mean (pseudo % CV) ^(c)Data in parentheses is thecoefficient of variance of the PK parameter (% CV), unless otherwiseindicated.

As can be seen from this data, the 30 mg ER tablet provided a lowerC_(max) and comparable AUC to the 24 mg dose IR capsule (2×12 mg) underfasting conditions.

The relative bioavailability for a single dose of the once-daily (ER)tablet formulation (Regimen D) relative to the IR capsule formulations(Regimen C) was also determined based on analysis of the naturallogarithms of C_(max) and AUC. The results are summarized in Table 46-Bbelow.

TABLE 46-B Relative Bioavailability and 90% Confidence Intervals forBioequivalence Assessment PK Value Relative Bioavailability PK Regimen CPoint 90% Confidence Parameter Regimen D (reference) Estimate IntervalC_(max) 63.7 176 0.368 0.326-0.415 AUC_(t) 477 520 0.912 0.828-1.004AUC_(inf) 491 524 0.933 0.845-1.029

For Regimen D versus Regimen C, the point estimates for the ratios ofAUC_(t) and AUC_(inf) were near unity, and the 90% confidence intervalswere within the 0.82-1.03 range.

Example 47: Comparison of the In Vivo Pharmacokinetic Profile of 30 mgExtended Release Tablets Under Fasting Versus Fed Conditions

The pharmacokinetic profile of the 30 mg extended release tabletsprepared in Example 31 after a high-fat meal was evaluated, and comparedto the pharmacokinetic profile of the 30 mg extended release tabletsunder fasting conditions (see Example 46).

Following completion of the Example 46 study, the healthy human subjects(n=12) were administered single doses of the 30 mg ER (once daily)tablet from Example 31 after a high-fat meal (Regimen E). Serial bloodsamples were collected from each subject prior to dosing and for 72hours after dosing. Upon collection, the samples were promptly placed inan ice bath, and within 2 hours after sample collection they werecentrifuged at about 4° C. The resulting plasma samples were placed inclean polypropylene-tubes and stored in a freezer until analysis. Theplasma samples were assayed for Compound 1 using appropriate liquidchromatography mass spectrometry procedures.

Pharmacokinetic parameters were estimated using non-compartmentalmethods, and summary statistics were computed for each parameter, andcompared to the pharmacokinetic parameters for the 30 mg tabletsadministered under fasting conditions (see Example 46, Regimen D). Theresults are summarized in Table 47-A. The mean concentration of Compound1 at each time point using linear (FIG. 18A) and semi-log (FIG. 18B)scales for each of the two regimens is set forth in FIGS. 18A and 18B.

TABLE 47-A Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of 30 mg ER Tablet Under Fasting Conditions orAfter a High-Fat Meal Regimen D Regimen E PK Parameter Units (Fasting)(After High-Fat Meal) C_(max) ng/mL 63.7 (33) 76.8 (39) T_(max) ^(a)hours 2.0 (1.5-4.0) 4.0 (1.5-8.0) t_(1/2) ^(b) hours 10.8 (67) 11.9 (51)AUC_(t) ng · h/mL 477 (27) 564 (26) AUC_(inf) ng · h/mL 491 (27) 577(27) ^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-CV %)^(c)Data in parentheses is coefficient of variance of the PK parameter(% CV), unless otherwise indicated.

The relative bioavailability for a single dose of the once-daily (ER) 30mg tablet formulation after a high-fat meal (Regimen E) relative to thebioavailability of the ER 30 mg tablet under fasting conditions (RegimenD) was also determined based on analysis of the natural logarithms ofC_(max) and AUC. The results are summarized in Table 47-B below.

TABLE 47-B Relative Bioavailability and 90% Confidence Intervals forBioequivalence Assessment PK Value Regimen E Relative Bioavailability PK(after high- Regimen D Point 90% Confidence Parameter fat meal)(fasting) Estimate Interval C_(max) 76.8 63.7 1.197 1.027-1.395 AUC_(t)564 477 1.184 1.042-1.344 AUC_(inf) 577 491 1.171 1.035-1.326

As can be seen from Tables 47-A and 47-B, there is no clinicallymeaningful food effect for the 30 mg ER tablets. Administrationfollowing a high-fat meal increased the Compound 1 mean AUC and C_(max)by 17% and 20%, respectively.

Example 48: Observed Steady State Exposures for 15 mg and 30 mg ExtendedRelease Tablets Under Non-Fasting Conditions

The steady state pharmacokinetic profile of the 15 mg once dailyextended release (ER) tablets (prepared in Example 28) and the 30 mgonce daily ER tablets (prepared in Example 31) was evaluated.

Healthy human subjects (n=24) were assigned to one of two regimens.Subjects in Regimen F (n=12) were administered the 15 mg ER tablet fromExample 28 once daily for seven days under non-fasting conditions.Subjects in Regimen G (n=12) were administered the 30 mg ER tablet fromExample 31 once daily for seven days under non-fasting conditions. Ondays one and seven, serial blood samples were collected from eachsubject prior to the daily dosing and up to 24 hours after dosing. Uponcollection, the samples were promptly placed in an ice bath, and within2 hours after sample collection they were centrifuged at about 4° C. Theresulting plasma samples were placed in clean polypropylene-tubes andstored in a freezer until analysis. The plasma samples were assayed forCompound 1 using appropriate liquid chromatography mass spectrometryprocedures. Pharmacokinetic parameters were estimated usingnon-compartmental methods, and summary statistics were computed for eachparameter by regimen.

The results are summarized in Table 48-A. The mean plasma concentrationof Compound 1 at each time point measured for each of the two regimensis set forth in FIG. 19.

TABLE 48-A Mean (% CV)^(e) Pharmacokinetic Parameters for Compound 1Following Administration of 15 mg ER Tablet or 30 mg ER Tablet QD forSeven Days (Non-Fasting) Regimen F Regimen G (15 mg ER Tablet) (30 mg ERTablet) PK Parameter Units Day 1 Day 7 Day 1 Day 7 C_(max) ng/mL 36.8(26) 36.0 (24) 74.3 (32) 79.5 (40) T_(max) ^(a) hours 4.0 (3.0-6.0) 4.0(2.0-6.0) 4.0 (2.0-6.0) 4.0 (1.5-6.0) AUC₂₄ ng · h/mL 305 (24) 317 (21)517 (30) 582 (30) C₂₄ ng/mL 2.42 (45) 3.22 (46) 4.27 (48) 5.25 (44)C_(trough) ng/mL — 2.96 (35) — 5.02 (42) C_(min, SS) ng/mL — 2.80 (41) —4.62 (38) Fluctuation Index % 291 (14) 251 (14) 345 (14) 306 (17)t_(1/2) ^(b) hours — 9.43 (76) — 10.4 (44) C_(max) to C₂₄ ratio 17(7.8-44) 13 (5.6-35) 17 (9.9-38) 14 (7.0-30) C_(max)/Dose (ng/mL)/mg2.46 (26) 2.40 (24) 2.48 (32) 2.65 (40) C_(trough)/Dose (ng/mL)/mg 0.16(45) 0.21 (46) 0.14 (48) 0.18 (44) AUC₂₄/Dose (ng · h/mL)/mg 20.3 (24)21.2 (21) 17.2 (30) 19.4 (30) R_(AUC) ^(c) — 1.02 (0.91-1.40) — 1.16(0.92-1.31) R_(Cmax) ^(d) — 1.00 (0.84-1.26) — 1.02 (0.82-1.40)^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-% CV) ^(c)R_(AUC)= AUC₂₄Day 7/AUC₂₄Day 1; median (range) ^(d)R_(Cmax) = C_(max)Day7/C_(max)Day 1; median (range) ^(e)Data in parentheses is thecoefficient of variance of the PK parameter (% CV), unless otherwiseindicated

As can be seen from this data, the observed steady state C_(max) andAUC₂₄ following 15 mg QD and 30 mg QD administration are generallyconsistent with the single dose and food-effect results obtained inExamples 45-47. The bioavailability of the 15 mg and 30 mg ER tablets is70% to 80% relative to the same dose of IR capsules.

Example 49: Observed Steady State Exposures for 15 mg Extended ReleaseTablets and 6 mg Immediate Release Capsules Under Fasting Conditions

The steady state pharmacokinetic profile of the 15 mg once dailyextended release (ER) tablets (prepared in Example 28) under fastingconditions was evaluated, and compared to that of a 6 mg immediaterelease (IR) twice daily (BID) capsule comprising Tartrate Hydrate asthe active.

Healthy human subjects were assigned to one of two regimens underfasting conditions in a randomized, two-period, cross-over study design.Subjects in Regimen K (n=12 at onset; n=11 on Day 7) were administeredthe 6 mg IR capsule twice daily for seven days under fasting conditions.Subjects in Regimen L (n=12) were administered the 15 mg ER tablet fromExample 28 once daily for seven days under fasting conditions. On daysone and seven, serial blood samples were collected from each subjectprior to the daily dosing and up to 24 hours after dosing. Blood sampleswere also collected at 48, 72, 96 and 120 hours after initial dosing.Upon collection, the samples were promptly placed in an ice bath, andwithin 2 hours after sample collection they were centrifuged at about 4°C. The resulting plasma samples were placed in clean polypropylene-tubesand stored in a freezer until analysis. The plasma samples were assayedfor Compound 1 using appropriate liquid chromatography mass spectrometryprocedures. Pharmacokinetic parameters were estimated usingnon-compartmental methods, and summary statistics were computed for eachparameter by regimen.

The results are summarized in Table 49-A. The mean plasma concentrationof Compound 1 at each time point measured for each of the two regimensis set forth in FIG. 20.

TABLE 49-A Mean (% CV)^(e) Pharmacokinetic Parameters for Compound 1Following Administration of 6 mg BID (IR) Capsules and 15 mg QD (ER)Tablets for Seven Days (Fasting Conditions) Regimen K Regimen L (6 mg IRCapsules (BID)) (15 mg ER Tablet (QD)) PK Parameter Units Day 1 Day 7Day 1 Day 7 C_(max) ng/mL 36.5 (25) 33.9 (26) 31.7 (40) 31.9 (35)T_(max) ^(a) hours 1.0 (1.0-13) 1.0 (0.5-14) 3.0 (1.5-6.0) 2.5 (1.5-4.0)AUC₂₄ ng · h/mL 289 (21) 288 (22) 249 (29) 279 (26) C₁₂ ng/mL 2.0 (30)2.8 (24) — — C₂₄ ng/mL 3.2 (36) 3.6 (23) 1.9 (42) 3.1 (37) C_(min) ng/mL— 2.7 (26) — 3.1 (37) Fluctuation Index % 303 (13) 259 (13) 299 (22) 246(21) t_(1/2) ^(b) hours — 14.7 (77) — 10.3 (76) C_(max) to C₂₄ ratio^(a)— 12 (7.7-19) 8.8 (7.4-13) 22 (5.8-43) 12 (4.2-20) C_(max) to C_(min)ratio^(a) — — 13 (8.3-18) — 12 (4.2-20) AUC₂₄/Dose (ng · h/mL)/mg 24.8(23) 24.0 (22) 16.6 (29) 18.6 (26) R_(AUC) ^(c) — — 1.02 (0.88-1.09) —1.11 (0.87-1.99) R_(Cmax) ^(d) — — 0.97 (0.68-1.17) — 1.01 (0.65-3.01)^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-% CV) ^(c)R_(AUC)= AUC₂₄Day 7/AUC₂₄Day 1; median (range) ^(d)R_(Cmax) = C_(max)Day7/C_(max)Day 1; median (range) ^(e)Data in parentheses is thecoefficient of variance of the PK parameter (% CV), unless otherwiseindicated

The relative bioavailability for the once-daily (ER) tablet formulation(Regimen L) relative to the twice daily (IR) capsule formulation(Regimen K) at steady state was also determined based on analysis of thenatural logarithms of C_(max), AUC₂₄, C_(mm), and C₂₄. The results aresummarized in Table 49-B below.

TABLE 49-B Relative Bioavailability Estimates and 90% ConfidenceIntervals for 15 mg QD Tablets Relative to 6 mg BID Capsules at SteadyState under Fasting Conditions Relative Bioavailability 90% ConfidencePK Parameter Point Estimate Interval C_(max) 0.909 0.736-1.122 AUC₂₄0.939 0.837-1.053 C_(min) 1.090 0.852-1.395

The ratio of steady-state AUC for the 15 mg QD tablets relative to the 6mg BID capsules was approximately 1, with the 90% confidence intervalswithin the equivalence boundaries. The ratio of the steady-state C_(min)was approximately 1 for the 15 mg QD tablet relative to the 6 mg BIDcapsules.

The pre-morning dose trough concentration (C_(trough)) for the 6 mg BIDcapsules and 15 mg QD tablets was determined prior to the morning doseon Days 2-8. The results are set forth in FIG. 21.

As can be seen from this data, at steady state under fasting conditions,the 15 mg QD tablets provided equivalent AUC₂₄ and comparable C_(max)and C_(min) relative to the 6 mg BID capsules. The steady state C_(max)was 10% lower for the 15 mg QD tablet compared to the 6 mg BID capsule.

Example 50: Observed Steady State Exposures for 30 mg Extended ReleaseTablets and 12 mg Immediate Release Capsules Under Fasting Conditions

The steady state pharmacokinetic profile of the 30 mg once dailyextended release (ER) tablets (prepared in Example 31) under fastingconditions was evaluated, and compared to that of a 12 mg immediaterelease (IR) twice daily (BID) capsule comprising Tartrate Hydrate asthe active.

Healthy human subjects were assigned to one of two regimens underfasting conditions in a randomized, two-period, cross-over study design.Subjects in Regimen M (n=11) were administered the 12 mg IR capsuletwice daily for seven days under fasting conditions. Subjects in RegimenN (n=12 at onset; n=11 at Day 7) were administered the 30 mg ER tabletfrom Example 31 once daily for seven days under fasting conditions. Ondays one and seven, serial blood samples were collected from eachsubject prior to the daily dosing and up to 24 hours after dosing. Bloodsamples were also collected at 48, 72, 96 and 120 hours after initialdosing. Upon collection, the samples were promptly placed in an icebath, and within 2 hours after sample collection they were centrifugedat about 4° C. The resulting plasma samples were placed in cleanpolypropylene-tubes and stored in a freezer until analysis. The plasmasamples were assayed for Compound 1 using appropriate liquidchromatography mass spectrometry procedures. Pharmacokinetic parameterswere estimated using non-compartmental methods, and summary statisticswere computed for each parameter by regimen.

The results are summarized in Table 50-A. The mean plasma concentrationof Compound 1 at each time point measured for each of the two regimensis set forth in FIG. 22.

TABLE 50-A Mean (% CV)^(e) Pharmacokinetic Parameters for Compound 1Following Administration of 12 mg BID (IR) Capsules and 30 mg QD (ER)Tablets for Seven Days (Fasting Conditions) Regimen M Regimen N (12 mgIR Capsules (BID)) (30 mg ER Tablet (QD)) PK Parameter Units Day 1 Day 7Day 1 Day 7 C_(max) ng/mL 80.8 (23) 73.9 (19) 65.7 (22) 68.2 (30)T_(max) ^(a) hours 1.0 (0.5-13) 1.0 (0.5-1.5) 2.5 (1.5-4.0) 3.0(2.0-4.0) AUC₂₄ ng · h/mL 497 (15) 534 (18) 454 (23) 525 (23) C₁₂ ng/mL3.0 (46) 4.1 (55) — — C₂₄ ng/mL 6.5 (54) 6.9 (37) 2.8 (37) 4.4 (39)C_(min) ng/mL — 3.8 (58) — 3.8 (43) Fluctuation Index % 388 (15) 317(14) 349 (12) 291 (17) t_(1/2) ^(b) hours — 7.3 (60) — 14.4 (64) C_(max)to C₂₄ ratio^(a) — 15 (5.4-20) 12 (5.9-16) 29 (13-38) 17 (4.1-33)C_(max) to C_(min) ratio^(a) — — 19 (8.4-31) — 17 (11-37) AUC₂₄/Dose (ng· h/mL)/mg 21.1 (15) 22.3 (18) 15.1 (22) 17.5 (23) R_(AUC) ^(c) — — 1.08(0.97-1.18) — 1.11 (0.79-1.67) R_(Cmax) ^(d) — — 0.98 (0.65-1.18) — 1.03(0.40-1.82) ^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-% CV)^(c)R_(AUC) = AUC₂₄Day 7/AUC₂₄Day 1; median (range) ^(d)R_(Cmax) =C_(max)Day 7/C_(max)Day 1; median (range) ^(e)Data in parentheses is thecoefficient of variance of the PK parameter (% CV), unless otherwiseindicated

The relative bioavailability for a single dose of the once-daily (ER)tablet formulation (Regimen N) relative to the twice daily (IR) capsuleformulation (Regimen M) was also determined based on analysis of thenatural logarithms of C_(max), AUC₂₄, C_(min), and C₂₄. The results aresummarized in Table 50-B below.

TABLE 50-B Relative Bioavailability Estimates and 90% ConfidenceIntervals for 30 mg QD Tablets Relative to 12 mg BID Capsules at SteadyState under Fasting Conditions Relative Bioavailability 90% ConfidencePK Parameter Point Estimate Interval C_(max) 0.900 0.732-1.107 AUC₂₄0.974 0.869-1.092 C_(min) 0.874 0.747-1.022

The ratio of steady-state AUC for the 30 mg QD tablets relative to the12 mg BID capsules was approximately 1, with the 90% confidenceintervals within the equivalence boundaries. The steady-state C_(min)for the 30 mg QD tablet was approximately 13% lower than for the 12 mgBID capsules. Outliers with high C_(min) in the 12 mg BID dose may havecontributed to this difference.

The pre-morning dose trough concentration (C_(trough)) for the 12 mg BIDcapsules and 30 mg QD tablets was determined prior to the morning doseon Days 2-8. The results are set forth in FIG. 23. As can be seen fromthis data, at steady state under fasting conditions, the 30 mg QDtablets provided equivalent AUC₂₄ and comparable C_(max) and C_(min)relative to the 12 mg BID capsules. The steady state C_(max) was 10%lower for the 30 mg QD tablet compared to the 12 mg BID capsules.

Example 51: Comparison of AM vs. PM Pharmacokinetic Profile FollowingAdministration of 6 mg or 12 mg Immediate Release Capsules Under FastingConditions

The pharmacokinetic profile of the 6 mg immediate release (IR) twicedaily (BID) capsules and the 12 mg IR twice daily capsules wasdetermined on Day 7 of Regimen K (Example 49) and Regimen M (Example50), respectively, after administration of the morning (AM dose) andevening (PM dose). The results are summarized in Table 51-A.

TABLE 51-A Mean (% CV)^(b) Pharmacokinetic Parameters for Compound 1Following Administration of AM and PM Doses of 6 mg and 12 mg ImmediateRelease Capsules on Day 7 (Fasting Conditions) Regimen K Regimen M (6 mgIR Capsules) (12 mg IR Capsules) PK Parameter Units AM Dose PM Dose^(c)AM Dose PM Dose^(c) C_(max) ng/mL 33.6 (28) 24.4 (22) 73.9 (19) 46.0(26) T_(max) ^(a) hours 1 (0.5-1.5) 2 (1.0-3.0) 1 (0.5-1.5) 3 (1.0-4.0)AUC₁₂ ng · h/mL 152 (26) 153 (19) 290 (19) 244 (19) C₁₂ ng/mL 2.76 (24)3.63 (23) 4.1 (55) 6.94 (37) C_(max)/C₁₂ — 12.3 (23) 6.9 (22) 18.0 (30)7.4 (39) ^(a)Median (Minimum-Maximum) ^(b)Data in parentheses is thecoefficient of variance of the PK parameter (% CV), unless otherwiseindicated ^(c)The PM dose was administered 3 hours after starting dinnerand 4 hours before a snack.

Example 52: Evaluation of the In Vivo Pharmacokinetic Profile of 30 mgExtended Release Tablets

The pharmacokinetic profiles of the 30 mg once-daily extended release(ER) tablets that were prepared in Examples 37 (ER10, 30% tartaricacid), 38 (ER11, 20% tartaric acid), and 39 (ER12, 10% tartaric acid)using wet granulation were evaluated, and compared to that of the 30 mgER tablet that was prepared in Example 31 (ER8, 30% tartaric acid) usingdirect compression (no wet granulation). The effect of a high-fat mealon the Example 37, 38, and 39 formulations was also evaluated.

Healthy human subjects (n=36) were administered a single dose of the 30mg ER (once daily) tablet from Example 31 (ER8), Example 37 (ER10),Example 38 (ER11), and Example 39 (ER12) under fasting conditions orafter a high-fat meal (non-fasting), in an open-label, randomized,four-period, incomplete crossover study. Doses in the four periods wereseparated by at least four days. Dosing regimens were as set forth belowin Table 52-A.

TABLE 52-A Dosing Regimens Regimen Dose Formulation Fasting/Non-FastingA Single 30 mg Example 31 (ER8) Fasting B Single 30 mg Example 37 (ER10)Fasting C Single 30 mg Example 37 (ER10) Non-Fasting D Single 30 mgExample 38 (ER11) Fasting E Single 30 mg Example 38 (ER11) Non-Fasting FSingle 30 mg Example 39 (ER12) Fasting G Single 30 mg Example 39 (ER12)Non-Fasting

Serial blood samples were collected from each subject prior to dosingand for 72 hours after dosing in each study period. Upon collection, thesamples were promptly placed in an ice bath, and within 1 hour aftersample collection they were centrifuged at about 4° C. The resultingplasma samples were placed in clean polypropylene-tubes and stored in afreezer until analysis. The plasma samples were assayed for Compound 1using appropriate liquid chromatography mass spectrometry procedures.Pharmacokinetic parameters were estimated using non-compartmentalmethods, and summary statistics were computed for each parameter byregimen.

Bioavailability Under Fasting Conditions

The results for administration under fasting conditions are summarizedin Table 52-B. The mean plasma concentration of Compound 1 at each timepoint using linear (FIG. 24A) and log-linear (FIG. 24B) scales for eachof the four fasting regimens is set forth in FIGS. 24A and 24B.

TABLE 52-B Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of a Single 30 mg Dose of Various Compound 1Once-Daily Formulations Prepared Using Wet Granulation Compared toAdministration of a Single 30 mg Dose of a Compound 1 Once-DailyFormulation Prepared Via Direct Compression Under Fasting ConditionsRegimen A Regimen B Regimen D Regimen F PK (ER8) (ER10) (ER11) (ER12)Parameter Units (n = 36) (n = 24) (n = 24) (n = 24) C_(max) ng/mL 57.0(33) 55.8 (27) 61.0 (25) 58.6 (34) T_(max) ^(a) hours 2.5 (1.0-4.0) 3.0(1.0-4.0) 2.0 (1.0-4.0) 2.0 (1.0-4.0) AUC_(t) ng · h/mL 495 (24) 473(24) 487 (22) 481 (23) AUC_(inf) ng · h/mL 513 (26) 484 (24) 499 (22)495 (23) t_(1/2) ^(b) hours 9.2 (61) 10.1 (50) 9.0 (61) 9.3 (63)^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-% CV) ^(c)Data inparentheses is coefficient of variance of the PK parameter (% CV),unless otherwise indicated.

The relative bioavailability for a single dose of the three once-daily(ER) tablet formulations prepared using wet granulation (Regimens B, D,and F) relative to the ER tablet prepared via direct compression (no wetgranulation) (Regimen A) was also determined based on analysis of thenatural logarithms of C_(max), AUC_(t), and AUC_(inf). The results aresummarized in Table 52-C below.

TABLE 52-C Bioavailability for Three Compound 1 Once-Daily FormulationsPrepared Using Wet Granulation (30 mg; ER10, ER11, ER12) Relative to aFormulation Prepared Via Direct Compression (30 mg, ER8) under FastingConditions Relative Bioavailability PK Point 90% Confidence RegimensParameter Estimate Interval Regimen B (ER10) vs. C_(max) 1.0240.917-1.143 Regimen A (ER8) AUC_(t) 0.990 0.933-1.049 AUC_(inf) 0.9760.918-1.037 Regimen D (ER11) vs. C_(max) 1.063 0.952-1.187 Regimen A(ER8) AUC_(t) 0.985 0.929-1.044 AUC_(inf) 0.977 0.919-1.038 Regimen F(ER12) vs. C_(max) 1.034 0.926-1.154 Regimen A (ER8) AUC_(t) 0.9580.904-1.016 AUC_(inf) 0.958 0.901-1.018

As can be seen from this data, all three of the 30 mg tablets preparedusing wet granulation (ER10, ER11, and ER12) were bioequivalent underfasting conditions to the tablet prepared via direct compression (no wetgranulation).

Effect of a High-Fat Meal on Example 37 Formulation (ER10)

The effect of a high-fat meal on the pharmacokinetic parameters of theExample 37 (ER10, 30 mg active, 30% tartaric acid) formulation issummarized in Table 52-D. The mean plasma concentration of Compound 1 ateach time point using linear (FIG. 25A) and log-linear (FIG. 25B) scalesfor each of Regimen B (ER10, fasting) and Regimen C (ER10, high-fatmeal) is set forth in FIGS. 25A and 25B. The change in Compound 1C_(max) and AUC_(inf) following administration of a single 30 mg dose ofthe ER10 tablet under fasting conditions and after a high-fat meal areshown in FIGS. 26A (C_(max)) and 26B (AUC_(inf)).

TABLE 52-D Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of Single 30 mg Dose of the Once-Daily TabletFormulation ER10 under Fasting Conditions and After High-Fat MealRegimen B Regimen C PK (ER10, fasting) (ER10, high fat meal) ParameterUnits (n = 24) (n = 12) C_(max) ng/mL 55.8 (27) 76.3 (30) T_(max) ^(a)hours 3.0 (1.0-4.0) 4.0 (1.5-8.0) AUC_(t) ng · h/mL 473 (24) 605 (23)AUC_(inf) ng · h/mL 484 (24) 609 (23) t_(1/2) ^(b) hours 10.1 (50) 9.1(35) ^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-% CV)^(c)Data in parentheses is coefficient of variance of the PK parameter(% CV), unless otherwise indicated.

The relative bioavailability for a single dose of the Example 37formulation (ER10) administered after a high-fat meal relative toadministration under fasting conditions was also determined based onanalysis of the natural logarithms of C_(max), AUC_(t), and AUC_(inf).The results are summarized in Table 52-E below.

TABLE 52-E Bioavailability of Single Dose of the 30 mg Once- DailyTablet ER10 Administered after High-Fat Meal Relative to under FastingConditions Relative Bioavailability PK Point 90% Confidence ParameterEstimate Interval Regimen C (ER10, C_(max) 1.322 1.134-1.541 high-fatmeal) vs. AUC_(t) 1.296 1.194-1.405 Regimen B (ER10, AUC_(inf) 1.2781.174-1.392 fasting)

As can be seen from this data, a high-fat meal increased the C_(max) andAUC_(inf) for the ER10 formulation (30 mg active, 30% tartaric acid) byabout 32% and 28%, respectively.

Effect of a High-Fat Meal on Example 38 Formulation (ER11)

The effect of a high-fat meal on the pharmacokinetic parameters of theExample 38 (ER11, 30 mg, 20% tartaric acid) formulation is summarized inTable 52-F. The mean plasma concentration of Compound 1 at each timepoint using linear (FIG. 27A) and log-linear (FIG. 27B) scales for eachof Regimen D (ER11, fasting) and Regimen E (ER11, high-fat meal) is setforth in FIGS. 27A and 27B. The change in Compound 1 C_(max) andAUC_(inf) following administration of a single 30 mg dose of the ER11tablet under fasting conditions and after a high-fat meal are shown inFIGS. 28A (C_(max)) and 28B (AUC_(inf)).

TABLE 52-F Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of Single 30 mg Dose of the Once-Daily TabletFormulation ER11 under Fasting Conditions and After High-Fat MealRegimen D Regimen E PK (ER11, fasting) (ER11, high fat meal) ParameterUnits (n = 24) (n = 12) C_(max) ng/mL 61.0 (25) 82.2 (33) T_(max) ^(a)hours 2.0 (1.0-4.0) 4.0 (3.0-8.0) AUC_(t) ng · h/mL 487 (22) 648 (24)AUC_(inf) ng · h/mL 499 (22) 657 (24) t_(1/2) ^(b) hours 9.0 (61) 9.7(53) ^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-% CV)^(c)Data in parentheses is coefficient of variance of the PK parameter(% CV), unless otherwise indicated.

The relative bioavailability for a single dose of the Example 38formulation (ER11) administered after a high-fat meal relative toadministration under fasting conditions was also determined based onanalysis of the natural logarithms of C_(max), AUC_(t), and AUC_(inf).The results are summarized in Table 52-G below.

TABLE 52-G Bioavailability of Single Dose of the 30 mg Once- DailyTablet ER11 Administered after High-Fat Meal Relative to under FastingConditions Relative Bioavailability PK Point 90% Confidence ParameterEstimate Interval Regimen E (ER11, C_(max) 1.343 1.153-1.563 high-fatmeal) vs. AUC_(t) 1.305 1.204-1.415 Regimen D (ER11, AUC_(inf) 1.2851.181-1.398 fasting)

As can be seen from this data, a high-fat meal increased the C_(max) andAUC_(inf) for the ER11 formulation (30 mg active, 20% tartaric acid) byabout 34% and 29%, respectively, which was a similar food effect as thatobserved for the Example 37 (ER10) tablet.

Effect of a High-Fat Meal on Example 39 Formulation (ER12)

The effect of a high-fat meal on the pharmacokinetic parameters of theExample 39 (ER12, 30 mg active, 10% tartaric acid) formulation issummarized in Table 52-H. The mean plasma concentration of Compound 1 ateach time point using linear (FIG. 29A) and log-linear (FIG. 29B) scalesfor each of Regimen F (ER12, fasting) and Regimen G (ER12, high-fatmeal) is set forth in FIGS. 29A and 29B. The change in Compound 1C_(max) and AUC_(inf) following administration of a single 30 mg dose ofthe ER12 tablet under fasting conditions and after a high-fat meal areshown in FIGS. 30A (C_(max)) and 30B (AUC_(inf)).

TABLE 52-H Mean (% CV) Pharmacokinetic Parameters for Compound 1Following Administration of Single 30 mg Dose of the Once-Daily TabletFormulation ER12 under Fasting Conditions and After High-Fat MealRegimen E Regimen G PK (ER12, fasting) (ER12, high fat meal) ParameterUnits (n = 24) (n = 12) C_(max) ng/mL 58.6 (34) 84.2 (33) T_(max) ^(a)hours 2.0 (1.0-4.0) 4.0 (4.0-6.0) AUC_(t) ng · h/mL 481 (23) 615 (24)AUC_(inf) ng · h/mL 495 (23) 622 (23) t_(1/2) ^(b) hours 9.3 (63) 11.7(91) ^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-% CV)^(c)Data in parentheses is coefficient of variance of the PK parameter(% CV), unless otherwise indicated.

The relative bioavailability for a single dose of the Example 39formulation (ER12) administered after a high-fat meal relative toadministration under fasting conditions was also determined based onanalysis of the natural logarithms of C_(max), AUC_(t), and AUC_(inf).The results are summarized in Table 52-I below.

TABLE 52-I Bioavailability of Single Dose of the 30 mg Once- DailyTablet ER12 Administered after High-Fat Meal Relative to under FastingConditions Relative Bioavailability PK Point 90% Confidence ParameterEstimate Interval Regimen G (ER12, C_(max) 1.527 1.314-1.774 high-fatmeal) vs. AUC_(t) 1.295 1.196-1.402 Regimen F (ER12, AUC_(inf) 1.2721.171-1.381 fasting)

As can be seen from this data, a high-fat meal increased the C_(max) andAUC_(inf) for the ER12 formulation (30 mg active, 10% tartaric acid) byabout 53% and 27%, respectively.

Example 53: Predicted Pharmacokinetic Parameters for 15 mg ExtendedRelease Tablets

The mean pharmacokinetic parameters under fasting conditions for theonce daily (QD) 15 mg extended release tablets prepared in Examples 40(ER13), 41 (ER14), and 42 (ER15) using wet granulation were extrapolatedfrom the single dose data obtained in Example 52 for the Examples 37(ER10), 38 (ER11), and 39 (ER12) formulations, respectively, underfasting conditions. The results are set forth in Table 53-A.

TABLE 53-A Predicted Mean Pharmacokinetic Parameters under FastingConditions for Compound 1 Following Administration of Single 15 mgOnce-Daily Formulations (Extrapolated from Single-Dose Profiles inExample 52 for 30 mg Doses) Single 15 mg Single 15 mg Single 15 mg PKParameters Units Dose (ER 13) dose (ER14) dose (ER15) C_(max) ng/mL 27.930.5 29.3 T_(max) ^(a) h 3.0 2.0 2.0 AUC_(inf) ng · h/mL 242 250 248^(a)Median (minimum-maximum)

Example 54: Preliminary Data from Phase 1 Study in Healthy Volunteersand Patients with Rheumatoid Arthritis

Compound 1 has been studied in 2 Phase 1 studies, first in human singleascending dose study (Study M13-401, described in WO 2015/061665, andreferred to herein as Study 1), and then in a multiple ascending dosestudy (Study M13-845, also generally referred to in WO 2015/061665, andreferred to herein as Study 2).

In Study 1, a total of 42 healthy volunteers received a single dose ofCompound 1. In Study 2, a total of 32 healthy volunteers receivedmultiple doses of Compound 1 for 14 days (Study 2, Part 1). In addition,14 patients with RA were enrolled and completed the double-blind Part 2of Study 2. The study was designed as a multiple-dose, randomized,multicenter trial, with the primary objective as assessing the safety,tolerability, and PK of multiple ascending doses of Compound 1 inhealthy adult volunteers and to assess the safety, tolerability, and PKof multiple doses of Compound 1 in patients with RA who are on a stablemethotrexate regimen.

Details of Study 1 and Study 2 and results obtained therefrom areprovided below.

Study 1—Single-Dose Escalation in Healthy Subjects

Study 1 was a single-dose escalation evaluation of Compound 1. Study 1was designed as a single-site, randomized, double-blind,placebo-controlled study. Fifty-six subjects in general good health wererandomized to receive single doses of Compound 1 immediate releasecapsules comprising Tartrate Hydrate (1, 3, 6, 12, 24, 36, and 48 mg) orplacebo in a 3:1 ratio with 8 subjects in each dose level. Study drugwas administered following at least 10 hours of fasting. The study wasconducted at PPD Development (Austin, Tex.). Subjects were confined tothe study site and supervised for approximately 8 consecutive days.Study protocol and informed consent were approved by RCRC institutionalreview board (IRB) (Austin, Tex.).

Study 2—Multiple-dose escalation

In Study 2, multiple twice-daily (BID) doses of immediate releasecapsules comprising Tartrate Hydrate were administered to healthysubjects (Part 1) or to subjects with rheumatoid arthritis (RA)receiving stable doses of methotrexate (Part 2). Both evaluationsfollowed randomized, double-blind, placebo-controlled designs. Part 1was conducted at PPD Development (Austin, Tex.) and Part 2 was conductedat two sites: Aspen Clinical Research (Orem, Utah) and Altoona Centerfor Clinical Research (Duncansville, Pa.). Study protocol and informedconsents were approved by RCRC IRB (Austin, Tex.) and Quorum Review IRB(Seattle, Wash.).

Study 2—Part 1—Multiple-Dose Escalation in Healthy Subjects

The objective of Part 1 of the multiple-dose study was to characterizethe pharmacokinetics, safety, and tolerability of multiple oral doses ofCompound 1 immediate release capsules comprising Tartrate Hydrate inhealthy subjects. Four escalating dosing regimens (3, 6, 12, and 24 mgCompound 1 or matching placebo twice daily for 13 consecutive days andonce in the morning on Day 14) were evaluated. Study drug wasadministered approximately 30 minutes after a standard breakfast (in themorning) or a snack (in the evening). Forty-four healthy subjectsparticipated in this part of the study with 11 subjects per dose group(8:3 Compound 1: placebo ratio). Subjects were confined to the studysite and supervised for approximately 18 days.

Study 2—Part 2—Multiple-Dose Evaluation in Subjects with RA

The objective of Part 2 of the multiple dose study was to assess thepharmacokinetics, safety, and tolerability of multiple oral doses ofCompound 1 immediate release capsules comprising Tartrate Hydrate insubjects with mild to moderate RA who were on stable methotrexatetreatment. This evaluation was designed to enroll approximately 32subjects randomized in a 1:1:1:1 ratio to one of four paralleltwice-daily regimens (6, 12, and 24 mg Compound 1 and placebo). Subjectsreceived study drug for 26 consecutive days (Study Days 3 through 28)and a single morning dose of study drug on Study Day 29. Compound 1 wasadministered following breakfast for the morning dose and dinner orsnack for the evening dose. Subjects were on methotrexate therapy for atleast 3 months and on a stable dose of 10 to 25 mg/week of methotrexatefor at least 4 weeks prior to the first dose of study drug administeredon Study Day 3 and continued their weekly stable dose of methotrexate onStudy Days 1, 8, 15, 22 and 29. Subjects were confined to the study sitefor a total of 10 days—from Day 1 to Day 4 and from Day 27 to Day 31.

Study Participants

Subjects underwent screening procedures within 30 days prior to theinitial administration of study drug. Subjects signed a written informedconsent prior to the initiation of any screening or study-specificprocedures. Subjects were eligible for study participation if they weremen or women between 18 and 55 years of age (Study 1 and Study 2—Part 1)or 18 to 75 years of age (Study 2—Part 2); judged to be in good generalhealth based upon the results of medical history, laboratory profile,physical examination, chest x-ray, and 12-lead electrocardiogram (ECG);and their body mass index (BMI) was within 19 to 29 kg/m² (Study 1 andStudy 2—Part 1) or within 19 to 39 kg/m² (Study 2—Part 2) at screening.Subjects were considered eligible to participate in Study 2—Part 2 ifthey had diagnosis of RA based on the 2010 American College ofRheumatology/European League against Rheumatism criteria≥6 months, havebeen on methotrexate therapy≥3 months (and folate or equivalent for atleast 2 weeks prior to Study Day 1), on a stable methotrexate dose of 10to 25 mg/week for at least 4 weeks prior to the first dose of study drugadministered on Study Day 3.

In both studies, subjects were excluded if they had any clinicallysignificant abnormalities, infection, major febrile illness,hospitalization, or had any clinically relevant surgical procedurewithin 30 days prior to the first dose of study drug; had positive testresult for hepatitis A virus immunoglobulin M, hepatitis B surfaceantigen, or hepatitis C virus antibody, or HIV antibodies at Screening;had history or evidence of active or latent tuberculosis; had history ofdiabetes or lymphoproliferative disease or evidence of immunosuppression(except for use of methotrexate in Study 2—Part 2); or had clinicallysignificant findings at Screening as determined by the principalinvestigator. Additionally, subjects in Study 2—Part 2 were excluded ifthey had a history of acute inflammatory joint disease of differentorigin other than RA or had current or expected need for oral intakeof >10 mg prednisone/day or equivalent corticosteroid therapy.

Pharmacokinetic Sampling

In healthy subjects, serial blood samples were collected over 72 hoursafter single dosing (Study 1) or over 12 hours after the first dose(Study Day 1) and over 72 hours after the last dose (Study Day 14) ofstudy drug (Study 2-Part 1). In subjects with RA, serial blood sampleswere collected over 48 hours on Study Day 1 for methotrexate assay, over12 hours following the first Study drug dose on Study Day 3 for Compound1 assay, over 12 hours following the morning Study drug dose on StudyDay 28 for Compound 1 assay, and over 48 hours following the last Studydrug dose on Study Day 29 for Compound 1 and methotrexate assays.Pre-dose trough samples were collected prior to the morning dose onStudy Days 5, 6, 7, 13, and 14 in Study 2—Part 1 to assess attainment ofsteady state.

Urine for Compound 1 assay was collected over a 12-hour interval afterthe last dose was administered on Study Day 14 in Study 2—Part 1 and onStudy Days 28 and 29 in Study 2—Part 2. Urine for methotrexate assay wascollected for 48 hours on Study Day 1 and Study Day 29.

Plasma and urine concentrations of Compound 1 and methotrexate weredetermined using validated liquid chromatography method with massspectrometric detection methods. The lower limits of quantitation (LLOQ)for Compound 1 and methotrexate in plasma were established at 0.0503ng/mL and 1.00 ng/mL, respectively. The LLOQ for Compound 1 andmethotrexate in urine were established at 1.01 ng/mL and 0.0500 μg/mL,respectively. Samples quantified below the LLOQ were reported as zero.For Compound 1 assays, inter-run variability (measured as % coefficientof variation [% CV]) was ≤9.5% for plasma≤8.4% for urine and the meanabsolute bias was ≤6.7% for plasma and ≤5.9% for urine. For methotrexateassay, inter-run variability (% CV) was ≤3.9% for plasma and ≤5.2% forurine and the mean absolute bias was ≤5.4% in plasma and ≤13.1% inurine.

Pharmacokinetic Analyses

Compound 1 and methotrexate pharmacokinetic parameters were determinedusing non-compartmental analyses with Phoenix software (Version 6.3,Certara, Princeton, N.J., USA). Calculated pharmacokinetic parametersincluded the maximum observed plasma concentration (C_(max)), time toC_(max) (T_(max)), trough plasma concentration (C_(trough)), theapparent terminal phase elimination rate constant (β), the terminalphase elimination half-life (t_(1/2)),the area under the plasmaconcentration-time curve (AUC) [from time 0 to time of the lastmeasurable concentration (AUC), from time 0 to infinity (AUC_(∞)) forsingle dosing, and over a 12-hour dosing interval (AUC₀₋₁₂, orAUC_(12,ss)) for multiple dosing and the apparent oral clearance (CL/F).Compound 1 functional half-life (t_(1/2)F) following multiple dosing wascalculated asln(2)/(ln[C_(max)/C_(troughl]/τ) at steady state, where τ is the) 12hour dosing interval (Dutta et al., Clin. Drug Investig., 2006, Vol.26(12), pp. 681-690). The accumulation ratio (R_(ac)) was calculated asthe ratio of Compound 1 AUC₀₋₁₂ on Day 14 to Day 1 (Study 2—Part 1) orDay 28 to Day 3 (Study 2—Part 2). The percentage of Compound 1 doserecovered unchanged in urine (f_(e) %) at steady state was calculated asthe amount of Compound 1 recovered in urine over the 0 to 12 hourinterval (Au, ₀₋₁₂), divided by the administered dose and multiplied by100. Renal clearance (CLr) was calculated as Au, ₀₋₁₂/AUC₀₋₁₂ at steadystate. Methotrexate f_(e) % was calculated as the amount of methotrexaterecovered in urine over the 0 to 48 hour interval (Au, ₀₋₄₈), divided bythe administered dose and multiplied by 100. CLr of methotrexate wascalculated as Au, ₀₋₄₈/AUC₀₋₄₈. The effect of co-administration ofmethotrexate on Compound 1 exposure was assessed from the ratios ofCompound 1 AUC₀₋₁₂ and C_(max) on Study Day 29 to Study Day 28. Theeffect of Compound 1 on methotrexate exposure was assessed from theratios of methotrexate AUC_(∞) and C_(max) on Study Day 29 to Study Day1.

Safety and Tolerability Assessment

Safety was evaluated based on assessments of adverse events, vitalsigns, physical examination, laboratory metrics, and 12-leadelectrocardiogram (ECG). All subjects who received at least one dose ofstudy drug were included in the safety analyses. Subjects who wereadministered placebo were pooled into a single group within each studyor study part. Laboratory test values and vital signs measurements thatwere above or below the reference range were identified. Subjects werefollowed-up for a total of 7 days in Study 1, 35 days in Study 2—Part 1,and 57 days in Study 2—Part 2. In healthy subjects, clinical adverseevents were graded as described in the Guidance for Industry ToxicityGrading Scale for Healthy Adult and Adolescent Volunteers Enrolled inPreventive Vaccine Clinical Trials (September 2007). In subjects withRA, the severity of adverse events were rated by the investigator asmild (transient and easily tolerated by the subject), moderate (causessubject discomfort and interrupts the subject's usual activities), orsevere (causes considerable interference with the subject's usualactivities and may be incapacitating or life-threatening). One subjectin Study 2—Part 2 was randomized to the placebo arm, but receivedCompound 1 in error on Study Days 10 to 16. Therefore, this subject wasincluded with the Compound 1 cohort for safety assessments

Statistical Analyses

Dose proportionality for Compound 1 in healthy subjects was tested usingthe natural logarithms of dose-normalized C_(max) and AUC followingsingle dosing (Study 1) or for steady-state dose-normalized C_(max),C_(trough), and AUC following multiple dosing (Study 2—Part 1)assessments. Attainment of steady-state following multiple doses inhealthy volunteers was assessed by testing the logarithmictransformation of Compound 1 morning pre-dose concentrations for StudyDays 5, 6, 7, 13, and 14 by repeated measures analysis. Statisticalanalyses were performed using SAS software (Version 9.3; SAS instituteInc., Cary, N.C., USA).

Results

Demographics and Subject Disposition

A total of 56 healthy subjects were enrolled in and completed thesingle-dose evaluation (Study 1) and 44 healthy subjects were enrolledin and completed the multiple-dose evaluation (Study 2—Part 1).Enrollment in the multiple-dose evaluation in subjects with RA (Study2—Part 2) was discontinued early due to slow recruitment rate and 14subjects with RA were actually enrolled and completed this evaluation.No early withdrawals occurred in any of the three evaluations. A summaryof demographic data is presented in Table 54-A.

TABLE 54-A Baseline Demographics of Study Participants Study 1 Study 2 -Part 1 Study 2 - Part 2 Compound 1 Placebo Compound 1 Placebo Compound 1Placebo N = 42 N = 14 N = 32 N = 12 N = 11 N = 3 Mean Age, 31.0 ± 9.8 32.4 ± 8.6 33.3 ± 9.9 30.7 ± 5.0  59.3 ± 8.3   58.7 ± 14.3 years ± SDMean Weight,  74.7 ± 10.1 74.3 ± 8.8 74.1 ± 9.9  78.4 ± 13.6  78.5 ±14.9 62.5 ± 6.9  kg ± SD Mean Height, 171 ± 8.9  171 ± 10.2  172 ± 7.9177 ± 6.2 171 ± 7.3 165 ± 9.9 cm ± SD Sex, number 35 males 11 males 29males 12 males 6 males 3 females (%) (83.3%), 7 (79%), 3 (91%), 3 (100%)(54.5%), 5 (100%) females females females (9%) females (16.7%) (21%)(45.5%) Race, number 30 White 11 White 23 White 9 White 10 White 2 White(%) (71%), 10 (79%), 3 (72%), 9 (75%), 2 (91%), 1 (67%), 1 Black (24%),Black (21%) Black (28%) Black (17%), Black (9%) Asian (33%) 1 Asian(2%), 1 Asian (8%) 1 Other (2%)

Compound 1 Single- and Multiple-Dose Pharmacokinetics in HealthyVolunteers

Compound 1 plasma concentrations reached peak levels at approximately 1to 2 hours after oral dosing of the immediate release capsuleformulation. Compound 1 plasma concentrations declined bi-exponentiallyafterwards with a terminal elimination t_(1/2) of approximately 6 to 15hours after single dosing (FIGS. 32A and 32B, Table 54-B) and of 8 to 16hours after multiple twice-daily dosing (FIG. 33, Table 54-C). Compound1 functional half-life, estimated from C_(max) to C_(trough) ratio atsteady-state, was approximately 3 hours. After multiple dosing, therewas a small but statistically significant (p<0.05) difference betweenCompound 1 pre-dose concentrations on Study Day 13 (13% lower) comparedwith Study Day 5. There was no statistically significant difference inCompound 1 pre-dose concentration on Study Day 13 and Study Day 14,indicating that steady-state was achieved by Study Day 13. Atsteady-state, the median accumulation ratios for Compound 1 AUC₀₋₁₂ wereapproximately 1.0 over the evaluated dose range (Table 54-C).

The relationships of dose-normalized C_(max) and AUC values versus dosefollowing single and multiple dosing are presented in FIGS. 34A-34D. Inthe single dose evaluation, 1 mg dose group was excluded from thestatistical analyses for AUC_(∞) as the majority of samples collected atthe terminal phase were below the limit of quantitation for allsubjects. There was no statistically significant difference indose-normalized C_(max) between the highest (48 mg) and the lowest (1mg) dose of Compound 1, and there was no statistically significant trendfor change in the dose-normalized C_(max) values with dose. There was notrend for change in Compound 1 dose-normalized AUC_(∞) with doses overthe 3 to 36 mg dose range (P>0.05); however the dose-normalized AUC_(∞)following single 48 mg dose was 40% lower than that following 3 mg dose(p<0.05).

Following multiple dosing in healthy subjects, there was nostatistically significant difference (p>0.05) in Compound 1dose-normalized steady-state C_(max), C_(trough), or AUC for the 24 mgtwice-daily regimen compared to the 3, 6, or 12 mg twice-daily regimens.

Overall, Compound 1 exposures appeared to be dose proportionalparticularly over the single dose range of 3 to 36 mg and the multipledose range of 3 mg to 24 mg BID.

TABLE 54-B Pharmacokinetic parameters (mean ± standard deviation) ofCompound 1 after administration of single doses of the immediate releaseformulation to healthy subjects Pharmacokinetic 1 mg 3 mg 6 mg 12 mg 24mg 36 mg 48 mg Parameters Cpd. 1 Cpd. 1 Cpd. 1 Cpd. 1 Cpd. 1 Cpd. 1 Cpd.1 (Units) (N = 6) (N = 6) (N = 6) (N = 6) (N = 6) (N = 6) (N = 6)C_(max) (ng/mL) 7.72 ± 2.36 25.0 ± 6.88 38.9 ± 9.96 82.9 ± 12.1 158 ±18.4  277 ± 44.5  314 ± 81.9 T_(max) (h)^(a) 1.3 (1.0-2.0) 1.0 (1.0-1.5)1.0 (1.0-1.5) 1.3 (0.5-1.5) 1.3 (1.0-1.5) 0.8 (0.5-1.0) 1.0 (0.5-1.0)t_(1/2) (h)^(b) — 5.9 ± 2.4 11.0 ± 3.4  12.1 ± 7.4  14.5 ± 9.0  6.4 ±4.0 12.2 ± 3.5 AUC_(t) (ng · h/mL) 29.8 ± 5.78  102 ± 27.5  159 ± 37.5 329 ± 48.9 612 ± 78.6 909 ± 201 1030 ± 174 AUC_(∞) (ng · h/mL) —  103 ±27.6  160 ± 37.6  331 ± 49.8 615 ± 78.1 911 ± 202 1040 ± 174 CL/F(L/h) —31.3 ± 10.4 39.1 ± 9.06 37.0 ± 6.32 39.5 ± 4.92  41.1 ± 8.35  47.6 ±8.97 ^(a)Median (range) ^(b)Terminal elimination half-life, presented asharmonic mean ± pseudo-standard deviation

TABLE 54-C Steady-State (Day 14) Pharmacokinetic parameters (mean ±standard deviation) of Compound 1 following administration of multipletwice-daily oral doses of the immediate release formulation to healthysubjects PK Parameters 3 mg BID 6 mg BID 12 mg BID 24 mg BID (Units) (N= 8) (N = 8) (N = 8) (N = 8) C_(max) (ng/mL) 18.5 ± 5.41 28.8 ± 3.6757.6 ± 11.0  119 ± 16.9 T_(max) (h) 1.5 (0.5-3.0) 2.0 (1.5-3.0) 2.3(1.5-3.0) 1.8 (1.5-2.0) AUC₀₋₁₂ 78.3 ± 20.3  138 ± 16.7  271 ± 52.7  529± 62.6 (ng · h/mL) C_(trough) (ng/mL) 1.46 ± 0.50 2.29 ± 0.41 4.54 ±1.55 9.50 ± 2.57 t_(1/2) (h)^(a) 15.7 ± 10.6 13.6 ± 8.5  7.6 ± 4.8 8.0 ±4.2 t_(1/2)F (h)^(b) 3.2 ± 0.4 3.3 ± 0.3 3.2 ± 0.5 3.3 ± 0.4 CL/F (L/h)40.7 ± 10.6 43.9 ± 5.4  45.5 ± 8.04 46.1 ± 6.44 CL_(r) (L/h)  7.5 ± 2.348.1 ± 1.8 9.7 ± 2.3 8.6 ± 2.8 f_(e) (%) 19 ± 5  19 ± 6  21 ± 4  19 ± 6 R_(ac) AUC₀₋₁₂ ^(c) 1.1 (0.9-1.2) 1.0 (0.9-1.2) 1.0 (0.9-1.1) 1.0(0.8-1.3) ^(a)Terminal elimination half-life. ^(b)Functional half-lifecalculated from C_(max) to C_(trough) ratio at steady state.^(c)Accumulation ratio for AUC₀₋₁₂. Harmonic mean ± pseudo-standarddeviation are presented for t_(1/2) and t_(1/2)F. Median and range(minimum to maximum) are presented for T_(max) and R_(ac) AUC₀₋₁₂. BID:twice-daily.

Compound 1 Multiple-Dose Pharmacokinetics in Subjects with RA

In subjects with RA who were on stable doses of methotrexate, Compound 1plasma concentrations reached peak levels at 1 to 2 hours after dosing(Table 54-D). The mean terminal elimination half-life of Compound 1ranged from approximately 10 to 14 hours, and the functional half-lifewas approximately 4 hours. The median accumulation ratio of Compound 1after 26 days of twice-daily dosing ranged from 0.8 to 1.4. The medianratio of Compound 1 C_(max) and AUC₀₋₁₂ when administered withmethotrexate (on Study Day 29) to those when administered withoutmethotrexate (Study Day 28) ranged from 0.9 to 1.2, indicating a lack ofsignificant effect of methotrexate co-administration on Compound 1pharmacokinetics (FIG. 35A). The steady-state dose-normalized C_(max)and AUC₀₋₁₂ of Compound 1 in subjects with RA compared to healthysubjects are presented in FIGS. 34B and 34D. The ratio of Compound 1exposure in subjects with rheumatoid arthritis to Compound 1 exposure inhealthy subjects ranged from 1.1 (24 mg twice-daily dose) to 1.6 (6 mgtwice-daily dose) for AUC₀₋₁₂ and from 1.2 (24 mg twice-daily dose) to1.7 (6 mg twice-daily dose) for C_(max).

TABLE 54-D Pharmacokinetic parameters (mean ± standard deviation) ofCompound 1 following administration of multiple twice-daily oral dosesto subjects with mild to moderate rheumatoid arthritis on stable dosesof methotrexate Compound 1 Compound 1 Compound 1 6 mg BID 12 mg BID 24mg BID PK (N = 4) (N = 3) (N = 3) Parameters Study Day (Units) Day 28Day 29 Day 28 Day 29 Day 28 Day 29 C_(max) (ng/mL) 47.1 ± 7.47 42.4 ±8.85 71.1 ± 14.8 60.8 ± 4.01  129 ± 39.0  154 ± 39.5 T_(max) (h) 1.5(1.0-2.0) 2.0 (1.5-3.0) 2.0 (1.5-2.0) 2.0 (1.5-3.0) 1.5 (1.5-4.0) 1.0(0.5-1.5) AUC₀₋₁₂  231 ± 48.5  215 ± 49.2  334 ± 49.4  338 ± 14.5 637 ±143  665 ± 89.8 (ng · h/mL) C_(trough) (ng/mL) 5.81 ± 3.06 4.63 ± 3.485.41 ± 0.98 6.44 ± 1.09 15.3 ± 1.86 14.9 ± 4.37 t_(1/2) (h)^(a) — 9.5 ±3.6 — 14.4 ± 5.3  — 11.5 ± 7.6  t_(1/2)F (h)^(b) — 3.5 ± 0.9 — 3.7 ± 0.2— 3.6 ± 0.1 CL/F (L/h) 26.7 ± 4.96 29.0 ±5.92 36.4 ± 5.44 35.6 ± 1.5639.1 ± 9.79 36.5 ± 4.70 CL_(r) (L/h) 6.94 ± 4.04 4.93 ± 2.41 6.27 ± 2.794.96 ± 3.34 6.31 ± 0.96 8.60 ± 1.30 f_(e) (%) 25 ± 14 16 ± 5  17 ± 8  14± 10 17 ± 5  24 ± 2  Rac AUC₀₋₁₂ ^(d)  14 (1.0-1.8) — 1.2 (0.9-1.4) —1.3 (1.2-1.4) — Day 29/Day 28 0.9 (0.9- 1.0) 1.0 (0.9-11) 1.0 (0.9-1.2)AUC₀₋₁₂ Ratio^(e) ^(a)Terminal elimination half-life. ^(b)Functionalhalf-life calculated from Cmax to Ctrough ratio at steady state.^(c)Accumulation ratio for AUC₀₋₁₂. Harmonic mean ± pseudo-standarddeviation are presented for t_(1/2) and t_(1/2)F. Median and range(minimum to maximum) are presented for T_(max), accumulation ratios, andDay 29/Day 28 ratios. BID: twice-daily

Effect of Compound 1 Co-Administration on Methotrexate Exposure

Pharmacokinetic parameters of methotrexate when administered before(Study Day 1) and after administration of multiple doses of Compound 1(Day 29) are summarized in Table 54-E. Since methotrexate wasadministered weekly and has a short plasma half-life, no plasmaaccumulation was expected with repeated dosing and AUC_(∞) wascalculated for both Days 1 and 29. The median ratio for methotrexateAUC_(∞) and C_(max) when administered after multiple doses of Compound 1(on Study Day 29) to that when administered without Compound 1 (on StudyDay 1) ranged from 0.9 to 1.1 and from 0.8 to 1.2, respectively. Therewas no observed change in methotrexate dose-normalized AUC_(∞) whenadministered with or without Compound 1 (FIG. 35B).

TABLE 54-E Pharmacokinetic parameters (mean ± standard deviation) ofmethotrexate following administration to subjects with RA alone (Day 1)or concomitant with Compound 1 (Day 29) Compound 1 Compound 1 Compound 16 mg BID Group 12 mg BID Group 24 mg BID Group Placebo (N = 4) (N = 3)(N = 3) (N = 4) PK Methotrexate Dose (mg) Parameters 16.3 ± 6.6 14.2 ±5.2 14.2 ± 1.4 17.5 ± 5.0 (Units) Day 1 Day 29 Day 1 Day 29 Day 1 Day 29Day 1 Day 29 C_(max)  245 ± 63.6  228 ± 23.0  278 ± 44.0  255 ± 99.9 196 ± 58.6  256 ± 29.3 318 ± 138 354 ± 182 (ng/mL) T_(max) (h) 2.5(1.5-6.0) 1.8 (1.0-2.0) 3.0 (2.0-3.0) 2.5 (2.5-3.0) 3.0 (0-3.0) 2.5(2.0-3.0) 1.8 (1.5-3.0) 1.8 (1.0-4.0) AUG_(∞) 1470 ± 494  1490 ± 424 1670 ± 393  1780 ± 791  966 ± 365 1370 ± 324  1640 ± 470  1590 ± 458 (ng · h/mL) t_(1/2) (h)^(a) 4.0 ± 2.6 4.7 ± 1.3 4.0 ± 0.3 4.2 ± 0.6 3.0± 1.1 3.1 ± 1.3 3.9 ± 0.5 3.8 ± 0.3 CL/F (L/h) 11.8 ± 6.43 10.9 ± 3.438.36 ± 1.28 8.14 ± 1.03 16.9 ± 8.89 10.6 ± 1.61 11.2 ± 3.81 11.3 ± 2.66CL_(r) (L/h) 6.63 ± 3.79 5.43 ± 2.02 6.13 ± 1.93 4.78 ± 2.28 7.46 ± 0.706.43 ± 0.75 4.32 ± 1.12 5.80 ± 1.08 f_(e) (%) 58 ± 29 51 ± 20 74 ± 19 59± 26 54 ± 25 63 ± 4  45 ± 25 57 ± 26 AUG_(∞) Ratio^(b) — 1.0 (0.8-1.4) —0.9 (0.9-1.3) — 1.1 (1.0-3.1) — 0.9 (0.8-1.2) ^(a)Terminal eliminationhalf-life presented as harmonic mean ± pseudo-standard deviation.^(b)Ratio of methotrexate exposure (AUC_(∞)) on Study Day 29 to that onStudy Day 1; median and range (minimum to maximum) are presented.

Safety and Tolerability

Across all three evaluations, a total of 74 healthy subjects and 11subjects with RA received Compound 1 and a total of 26 healthy subjectsand 3 subjects with RA received placebo. There were no dose-limitingtoxicities or safety concerns with Compound 1 from the single doses upto 48 mg or multiple doses up to 24 mg twice daily. Notably, the safetyand tolerability profile of Compound 1 was comparable between subjectswho received Compound 1 or placebo, and between healthy subjects andsubjects with RA on background treatment of methotrexate, though thenumber of subjects with RA was limited. There was no evidence of a doseor time dependency for the incidence of adverse events in either healthysubjects or subjects with RA. There were no study discontinuations dueto adverse events, no serious adverse events and no clinicallysignificant changes in ECG parameters, or laboratory metrics in any ofthe subjects or treatment groups. The maximum tolerated dose of Compound1 was not reached in the single or multiple dose studies. Adverse eventsthat were reported by at least two subjects in Compound 1 or placebogroups in Study 1 or Study 2—Part 1 are presented in Table 54-F.

TABLE 54-F Treatment-emergent adverse events reported by two or morehealthy subjects administered Compound 1 or placebo in the single andmultiple ascending dose evaluations Single doses (Study 1) System Organ1 mg 3 mg 6 mg 12 mg 24 mg 36 mg 48 ng Total Class MedDRA PlaceboCompound 1 Compound 1 Compound 1 Compound 1 Compound 1 Compound 1Compound 1 Compound 1 Preferred Term (N = 14) (N = 6) (N = 6) (N = 6) (N= 6) (N = 6) (N = 6) (N = 6) (N = 42) Any Adverse 3 (21.4%) 0 0 1(16.7%) 0 1 (16.7%) 2 (33.3%) 2 (33.3%) 6 (14.3%) Event Nervous 0 SystemDisorders Headache 0 0 0 0 0 0 0 2 (33.3%) 2 (4.8%) Presyncope* 0 0 0 1(16.7%) 0 1 (16.7%) 0 0 2 (4.8%) Multiple twice-daily doses (Study 2 -Part 1) 3 mg 6 mg 12 mg 24 mg Total System Organ Class Placebo Compound1 Compound 1 Compound 1 Compound 1 Compound 1 MedDRA Preferred Term (N =12) (N = 8) (N = 8) (N = 8) (N = 8) (n = 32) Any Adverse Event 7 (58.3%)2 (25.0%) 2 (25.0%) 3 (37.5%) 4 (50.0%)  11 (34.4%) GastrointestinalDisorders Abdominal Discomfort 3 (25.0%) 0 0 0 0 0 Abdominal Pain 0 0 1(12.5%) 0 1 (12.5%) 2 (6.3%) Diarrhoea 1 (8.3%)  0 1 (12.5%) 1 (12.5%) 02 (6.3%) Infections and Infestations Nasopharyngitis 2 (16.7%) 1 (12.5%)1 (12.5%) 0 0 2 (6.3%) Nervous System Disorders Headache 2 (16.7%) 0 2(25.0%) 2 (25.0%) 1 (12.5%)  5 (15.6%) *The two cases of presyncope wereassociated with venipuncture.

In healthy subjects who were administered single doses of eitherCompound 1 (1, 3, 6, 12, 24, 36, and 48 mg) or placebo in Study 1, 14.3%(6/42) and 21.4% (3/14) of subjects, respectively, reported to have oneor more treatment-emergent adverse events (TEAEs). All TEAEs wereassessed as mild in severity. The adverse events reported by more thanone subject who received Compound 1 were headache and presyncope (1subject in 6 mg and 1 subject in 24 mg dose group) in association withvenipuncture (see Table 54-F).

In healthy subjects who were administered multiple doses of Compound 1(3, 6, 12, and 24 mg BID) or placebo for 14 consecutive days in Study2—Part 1, 34% (11/32) and 58% (7/12) of subjects, respectively, reportedone or more TEAEs. The overall incidences of TEAEs were numericallyhigher at higher doses of Compound 1; 2 (25.0%), 2 (25.0%), 3(37.5%) and4 (50%) subjects in the 3 mg, 6 mg, 12 mg and 24 mg dose groups,respectively; however, these rates were lower than that was observed inthe placebo group (58%). All TEAEs were reported as mild in severity.Four events occurred in at least two subjects who received Compound 1:headache, abdominal pain, diarrhea, and nasopharyngitis; three of theseevents also occurred in subjects who received placebo: headache,diarrhea and nasopharyngitis (Table 54-F).

There were no clinically significant changes in any hematologicparameters after multiple-dose administration in healthy subjects for 14days. With increasing doses of Compound 1, there were statisticallysignificant downward trends in mean levels of hemoglobin, RBCs, WBCs andneutrophils; however, even at the 24 mg dose, the mean levels werewithin the normal reference range. The mean changes in reticulocytecounts with increasing dose of Compound 1 compared to placebo were notstatistically significant, suggesting no evidence of a dose relatedeffect on reticulocyte counts after 14 days of Compound 1 treatment.Total cholesterol, HDL-cholesterol, and LDL-cholesterol showed astatistically significant upward trend with increasing Compound 1 dosecompared with placebo; however, the final mean values for these lipidparameters in the Compound 1 dose groups remained within the normalreference range.

Subjects with mild to moderate RA on stable background doses ofmethotrexate, in Study 2-Part 2, were administered multiple doses ofCompound 1 (a total of 11 subjects) or placebo (a total of 3 subjects).Five subjects in the Compound 1 dose groups and two subjects in theplacebo group experienced at least one TEAE. In the Compound 1 dosegroups, 7 TEAEs were reported: nausea, vomiting, viral gastroenteritis,upper respiratory tract infection, post-traumatic neck syndrome, backpain, and insomnia. All TEAEs were reported by the investigators as mildor moderate in severity, and no adverse event was reported in more thanone subject in any treatment group. There was no evidence of a doserelationship with any of these events. Notably, as these subjects withRA received a stable background dose of methotrexate, there were nochanges in hepatobiliary metrics for those receiving Compound 1. Therewas also no evidence of a Compound 1 dose-related effect on renalfunction in these subjects with RA, as evaluated by serum creatinine andblood urea nitrogen values.

Discussion

Compound 1 was well-tolerated after single doses up to 48 mg andmultiple twice daily doses up to 24 mg of Compound 1 immediate-releaseformulation. All adverse events occurred after single- or multiple-doseadministrations were mild to moderate in nature with comparablefrequency between subjects who received Compound 1 or placebo. Noanemia, serious infections, or clinically significant changes inhematology, hepatobiliary or renal laboratory metrics was observed with14 days of repeated Compound 1 dosing in healthy volunteers or 27 daysof dosing in RA patients.

Compound 1 displayed multi-exponential plasma disposition with afunctional half-life of 3 to 4 hours across the dose range of 3 to 24 mgtwice daily of the immediate-release formulation in healthy volunteersand subjects with RA. The terminal elimination half-life of Compound 1ranged from 6 to 16 hours across the different dose levels. However,given the multi-exponential disposition of Compound 1, the longerterminal half-life is less relevant clinically than the functionalhalf-life (Dutta et al., Clin. Drug Investig., 2006, Vol. 26(12), pp.681-690; Sahin, Pharm. Res., 2008, Vol. 25(12), pp. 2869-77). Consistentwith a shorter functional half-life, there was no accumulation acrossthe evaluated 3 to 24 mg twice-daily dose range. While there are nosolid clinical data to suggest that extended exposure is needed forefficacy of JAK inhibitor (i.e. to determine whether efficacy isconcentration driven or AUC driven), the pharmacokinetic profile of theimmediate-release formulation of Compound 1 appears to be generally moresuited for twice-daily dosing than for once-daily dosing.

Compound 1 displayed dose-proportional pharmacokinetics particularlyover the 3 to 36 mg dose range (FIG. 34), which encompasses the doseranges evaluated in Phase 2b clinical trials in RA (3 to 18 mg BID and24 mg QD), or that is currently being evaluated in Crohn's disease (3 to24 mg BID).

It has been reported previously that the JAK inhibitors tofacitinib andfilgotinib have higher exposures in subjects with RA than those inhealthy volunteers (see FDA, “Clinical Pharmacology and BiopharmaceuticsReview(s)—Tofacitinib”, Application Number 203214Orig1s000, Center forDrug Evaluation and Research, 2011; Namour et al., Clin. Pharmacokinet.,2015, Vol. 54, pp. 859-874). Compound 1's apparent oral clearance was23% lower in subjects with RA (leading to approximately 30% higherexposure), on average across all dose groups, compared to healthysubjects. In general, older subjects are expected to have lower renaland metabolic capacity compared to younger subjects (Mangoni, Br. J.Clin. Pharmacol., 2004, Vol. 57(1), pp. 6-14). RA subjects who receivedmultiple-doses of Compound 1 were 26 years older, on average, than thehealthy subjects evaluated in Study 2 (Table 54-A); therefore, agecannot be excluded as potential contributor to the apparently 30% higherexposure of Compound 1 in RA subjects than in healthy subjects.

Methotrexate remains the first line therapy for treatment of RA and isoften used with biologic DMARDs or in combination with other csDMARDs(see Ma, et al., Rheumatology (Oxford), 2010, Vol. 49(1), pp. 91-8;Singh, et al., Arthritis Care Res. (Hoboken), 2012, Vol. 64(5), pp.625-39; Smolen, et al., Ann. Rheum. Dis., 2014, Vol. 73(3), pp.492-509). Therefore, at least in a subset of the RA patients, it isexpected that Compound 1 will be added to the first line therapy,methotrexate; thus, it was important to confirm a lack of any potentialinteraction between Compound 1 and methotrexate. The ratios of Compound1 AUC and C_(max) values when administered with methotrexate to thosewhen administered alone indicate lack of significant effect ofmethotrexate on Compound 1 (Table 54-D; FIG. 35A). Similarly, Compound 1did not have any significant effect on methotrexate exposures (Table54-E; FIG. 35B). This was consistent with the observed safety andtolerability profiles in these two populations.

In summary, Compound 1 displayed favorable safety and tolerabilityprofiles over single doses up to 48 mg and multiple doses up to 24 mgtwice daily for 14 days in healthy subjects and for 27 days in subjectswith RA. Compound 1 demonstrated a pharmacokinetic profile suitable fortwice-daily dosing with the immediate release formulation. There was nopharmacokinetic interaction between methotrexate and Compound 1 andthere was no accumulation of Compound 1 with repeated administration.

Example 55: Treatment of Moderately to Severely Active RheumatoidArthritis in Patients Who have Inadequately Responded to or areIntolerant to Anti-TNF Therapy

The following example briefly describes the results of a Phase 2b,12-week, randomized, double-blind, parallel-group, placebo-controlledstudy in which adult subjects with moderately to severely activerheumatoid arthritis (RA) who have inadequately responded to or who areintolerant to an anti-tumor necrosis factor (TNF) therapy were treatedwith Compound 1.

The study was conducted in accordance with the International Conferenceon Harmonisation guidelines, applicable regulations, and the principlesof the Declaration of Helsinki. The study protocol was approved by anindependent ethics committee or institutional review board. All patientsprovided written informed consent before participating in anystudy-related procedures.

Participants

Adult men and women aged 18 years or older, who had been diagnosed withRA and fulfilled either the 1987 revised American College ofRheumatology (ACR) classification criteria (Arnett et al, ArthritisRheum., 1988, Vol. 31(3), pp. 315-324) or the 2010 ACR/European LeagueAgainst Rheumatism (EULAR) criteria (Smolen et al, Ann. Rheum. Dis.,2010, Vol. 69(6), pp. 964-975) were enrolled in the study. Active RA wasdefined as subjects having ≥6 swollen joints (based on a 66-jointcount); ≥6 tender joints (based on a 68-joint count); andhigh-sensitivity C-reactive protein (hsCRP)>upper limit of normal (ULN=5mg/L) or seropositivity for both rheumatoid factor (RF) and anti-cycliccitrullinated peptide (CCP). Eligible subjects must have been treatedwith ≥1 anti-TNF biologic agent for ≥3 months but continued toexperience active RA, or discontinued anti-TNF biologic therapy becauseof intolerance or toxicity. In addition, subjects with prior exposure tonon-anti-TNF biologic therapy were allowed to enroll, as long as theyhad failed ≥1 anti-TNF biologic. All biologic therapies had to be washedout prior to randomization: ≥4 weeks for etanercept, ≥8 weeks foradalimumab, infliximab, certolizumab, and golimumab, ≥8 weeks forabatacept, ≥12 weeks for tocilizumab, and ≥1 year for rituximab. Astable dose of methotrexate (7.5-25 mg/week) was required throughout thestudy. Key exclusion criteria were prior exposure to a JAK inhibitor, ora need for any immunosuppressant other than methotrexate. Subjects withserum aspartate transaminase (AST) or alanine transaminase (ALT)>1.5×ULNor absolute neutrophil count (ANC)<1,200/μL or absolute lymphocytescount<750/μt at screening were excluded.

Study Design and Treatment

The study was a phase 2b, 12-week, randomized, double-blind,parallel-group, placebo-controlled study conducted at 123 sites,enrolling patients in the United States (176 patients, 64%) and PuertoRico (11 patients, 4%); Australia and New Zealand (6 patients, 2%);Western Europe including Belgium, Spain and Great Britain (29 patients,11%); Eastern Europe including Czech Republic, Hungary, Poland (54patients, 20%).

Subjects were equally randomized to receive oral immediate-release dosesof Compound 1 (immediate release capsules comprising Tartrate Hydrate)at 3 mg BID, 6 mg BID, 12 mg BID or 18 mg BID, or matching placebo BID,for 12 weeks. Randomization was performed centrally, according to ablocked randomization schedule, by investigators enrolling via aninteractive voice response system. Subjects, caregivers, investigators,joint assessors, and the study team were blinded to the treatmentadministered. Placebo and Compound 1 capsules were identical inappearance. Subjects should have been taking an oral supplement of folicacid (or equivalent) from four weeks prior to baseline and throughoutthe study. Subjects were allowed to continue stable doses ofmethotrexate and non-steroidal anti-inflammatory drugs (NSAIDS),acetaminophen, or oral corticosteroids (equivalent to prednisone≤10 mg).

Assessments

The primary efficacy endpoint was the proportion of subjects achievingan ACR20 response at Week 12. Secondary endpoints included theproportions of subjects achieving an ACR50/ACR70 response and theproportion of subjects achieving 28-joint count disease activity scorebased on C-reactive protein (DAS28(CRP))≤3.2, or <2.6, at Week 12. Amongthe other endpoints were the proportion of subjects achieving lowdisease activity (LDA) or clinical remission (CR) based on ClinicalDisease Activity Index (CDAI) criteria (LDA, CDAI≤10; CR, ≤2.8); changein DAS28(CRP), and change in the Health AssessmentQuestionnaire-Disability Index (HAQ-DI) (Anderson et al, Arthritis CareRes. (Hoboken), 2012, Vol. 64(5), pp. 640-647), including the proportionof subjects achieving minimal clinically important difference (MCID) of−0.22 (Strand et al, Rheumatology (Oxford), 2006, Vol. 45(12), pp.1505-1513). A post hoc analysis was performed to determine theproportion of subjects who had a sustained ACR20 response, defined asachievement of the ACR20 criteria at every visit (at Weeks 2, 4, 6, 8and 12).

Safety was evaluated at each scheduled visit during treatment and for 30days after the last dose of study drug on the basis of AEs, serious AEs,vital signs, and laboratory tests (hematology, blood chemistry, andurinalysis). Adverse events were coded according to the MedicalDictionary for Regulatory Activities (MedDRA, version 17.1).Descriptions of AE severity and post-baseline laboratory changes werebased on the Rheumatology Common Toxicity Criteria v.2.0, developed bythe OMERACT Drug Safety Working Group (Woodworth et al., 2007, J.Rheumatol., Vol. 34(6), ppl. 1401-14).

Statistical Methods

All efficacy analyses were conducted in modified intent-to-treatpopulation, which consisted of all randomized patients who received ≥1dose of study drug. For ACR response rates, the last observation carriedforward (LOCF) was the primary missing data imputation method andnon-responder imputation (NRI) was also used to assess the robustness ofthe results. For continuous endpoints including DAS28 (CRP), LOCFmissing data imputation was implemented; NRI is reported for binaryendpoints. Binary endpoints including ACR response rates were analyzedusing chi-square test with normal approximation when comparing eachCompound 1 treatment group to placebo group. Continuous endpoints wereanalyzed using an Analysis of Covariance (ANCOVA) model with treatmentgroup as a factor and baseline measurement as the covariate. TheMultiple Comparison Procedure and Modeling (MCPMod) method wasimplemented to detect any non-flat dose-response relationship byevaluating several non-linear dose-response models at the same time.P-values were not corrected for multiple comparisons.

Assuming ACR20 response rates of 25% in the placebo group and 55% in anyCompound 1 group, a sample size of 50 subjects per group (250 patientstotal) was estimated to provide at least 80% power to detect a 30%difference in response rates between the placebo group and an Compound 1group when using a 1-sided test with an alpha level of 0.05.

Results

Subject Disposition and Baseline Characteristics

In total, 276 subjects were randomized; all received their intendedtreatment. The overall study completion rate was 88% (FIG. 39). Baselinesubject characteristics and disease activity were generally similaramong treatment groups (see Table 55-A). The mean duration since RAdiagnosis was 12 years. Seventy-two percent of subjects had priorexposure to only one anti-TNF, 28% to ≥2 anti-TNFs, and 20% of subjectswere also exposed to non-anti-TNF biologics. At baseline, subjects hadmean swollen and tender joint counts of 18 (out of 66 joints) and 28(out of 68 joints), respectively; 60% subjects had an elevated hsCRP andmean DAS28(CRP) was 5.8.

TABLE 55-A Baseline Patient Characteristics and Disease ActivityCompound 1 3 mg 6 mg 12 mg 18 mg Placebo BID BID BID BID (n = 56) (n =55) (n = 55) (n = 55) (n = 55) Characteristic Female, number (%) 48 (86)43 (78) 43 (78) 44 (80) 42 (76) Age, years, mean (SD) 58 (12) 57 (13) 56(12) 59 (11) 57 (12) Duration since RA diagnosis, 12.1 (9.0) 11.8 (9.4)12.3 (10.6) 12.2 (10.2) 10.9 (7.7) years, mean (SD) RF positive, number(%) 49 (88) 43 (78) 45 (82) 45 (82) 48 (87) Anti-CCP positive, number 48(86) 45 (82) 45 (82) 45 (82) 47 (86) (%) Used ≥1 prior anti-TNF agent,42 (76) 39 (71) 38 (70) 38 (72) 38 (69) number (%) Used ≥2 prioranti-TNF agents, 13 (24) 16 (29) 16 (30) 15 (28) 17 (31) number (%) Usedprior non-anti-TNF 9 (16) 10 (18) 14 (26) 14 (26) 7 (13) agents, number(%)* Disease activity TJC68, mean (SD) 28 (15) 28 (15) 30 (16) 26 (16)26 (15) SJC66, mean (SD) 19 (12) 17 (10) 17 (10) 17 (10) 18 (10) HAQ-DI,mean (SD) 1.6 (0.7) 1.5 (0.7) 1.6 (0.7) 1.6 (0.6) 1.5 (0.6) DAS28(CRP),mean (SD) 5.8 (0.9) 5.7 (0.9) 5.9 (0.9) 5.7 (0.9) 5.8 (1.0) CDAI, mean(SD) 41 (12) 40 (13) 42 (12) 40 (12) 41 (14) hsCRP, mg/L, mean (SD)^(‡)10.1 (13.2) 11.4 (11.8) 18.6 (27.4) 14.4 (23.0) 14.0 (15.1) hsCRP >ULN,^(†) n (%)^(‡) 28 (50) 35 (64) 34 (62) 33 (60) 35 (64)Abbreviations: BID—twice daily; CDAI—Clinical Disease Activity Index;DAS28(CRP)—Disease Activity Score-28 joints using C-reactive protein;HAQ-DI—Health Assessment Questionnaire-Disability Index;hsCRP—high-sensitivity C-reactive protein; RA—rheumatoid arthritis;SJC66—swollen joint count using 66 joints; TJC68—tender joint countusing 68 joints; TNF—tumor necrosis factor; ULN—upper limit of normal.*Non-TNF biologic agents. ^(†)ULN = 5 mg/L. ^(‡)Subjects with normalhsCRP could be enrolled as long as they were positive for rheumatoidfactor and anti-cyclic citrullinated peptide. Modified intent-to-treatpopulation. Percentages were calculated using non-missing values.

Efficacy

The primary analysis based on LOCF revealed that an ACR20 response wasachieved by 55.6% (P=0.033), 63.5% (P=0.004), 72.7% (P<0.001), and 70.9%(P<0.001) in subjects treated with Compound 1 at 3, 6, 12, and 18 mgBID, respectively, compared with 35.2% in subjects who received placebo.Analysis based on NRI also demonstrated a statistically significantimprovement in ACR20 response rate in subjects who received any dose ofCompound 1 compared with those who received placebo (FIG. 36A). Asignificant dose-response relationship was observed for all doses ofCompound 1 (P<0.01). The ACR20 response rates (NRI) at Week 12 weresimilar among patients who had received 1 versus ≥2 prior anti-TNFs(FIG. 36B). ACR50 and ACR70 response rates were significantly higher atCompound 1 doses of ≥6 mg BID versus placebo (FIG. 36A).

Significant differences in ACR20 response rates (NRI) were observed atthe first post-baseline assessment (Week 2) in subjects treated withCompound 1 12 mg BID and 18 mg BID versus placebo (P<0.007; FIG. 37A);the maximum response rate (71%) was observed with the 12 mg BID dose byWeek 8 and plateaued thereafter. Starting at Week 4, there weresignificantly greater ACR50 response rates with Compound 1 doses≥6 mgBID versus placebo; the maximum response rate (42%) was observed withthe 18 mg BID dose by week 8 and plateaued thereafter (FIG. 37B).Improvements in ACR70 response rates better than placebo were observedstarting at Week 6, with peak response of up to 25% at Week 12 (FIG.37C). A sustained ACR20 response (at every visit between Week 2 through12, NRI) was achieved by 13%, 22%, 40% and 27% of subjects in theCompound 1 3 mg, 6 mg, 12 mg and 18 mg BID groups respectively, versus4% in the placebo group. Significant improvements in DAS28(CRP) (LOCF)occurred at the Week 2 assessment with Compound 1 at ≥6 mg BID versusplacebo (P<0.001; FIG. 37D).

A higher percentage of subjects receiving Compound 1 (any dose) achievedDAS28(CRP)≤3.2 or <2.6, versus placebo at Week 12 (NRI, FIGS. 37E and37F with the difference being statistically significantly for theCompound 1 12 mg BID group (DAS28(CRP)≤3.2, 49%; DAS28(CRP)<2.6, 33%,P<0.01) compared with placebo (25% and 13%, respectively). Similarly, ahigher percentage of patients treated with any dose of Compound 1achieved CDAI LDA or CR criteria versus placebo at Week 12 (NRI, FIG.37F). At Week 12, treatment with Compound 1 at 12 mg BID also resultedin statistically significant mean changes from baseline in individualcomponents of the ACR score compared with placebo (Table 55-B). Inaddition, a significantly greater proportion of patients achieved theMCID for HAQ-DI with Compound 1≥6 mg BID (58%-64%) as compared withplacebo (44%).

TABLE 55-B Mean Changes From Baseline in ACR Components at Week 12Compound 1 Placebo 3 mg BID 6 mg BID 12 mg BID 18 mg BID ACR Component(n = 55) (n = 54) (n = 53) (n = 55) (n = 55) TJC68 −9.3 (−12.5, −13.4(−16.6, −15.7** (−19.0, −16.8** (−20.1, −15.1* (−18.3, −6.1) −10.1)−12.5) −13.6) −11.9) SJC66 −6.4 (−8.7, −9.5 (−11.8, −9.2 (−11.4, −10.0*(−12.3, −9.2 (−11.5, −4.2) −7.2) −6.9) −7.8) −7.0) Patient's −16.5(−23.5, −24.7 (−31.8, −31.4**,^(†) (−38.6, −36.3*** (−43.3, −35.0***(−42.0, assessment of pain −9.5) −17.6) −24.2) −29.3) −27.9) PhGA −29.6*(−35.3, −33.8 (−39.4, −37.5 (−43.2, −43.5*** (−49.1, −42.4** (−48.0,−23.8) −28.1) −31.7) −37.9) −36.8) PtGA −20.0 (−27.0, −24.2 (−31.3,−29.9^(†) (−37.1, −37.4*** (−44.4, −33.5**,^(†) (−40.6, −13.0) −17.1)−22.6) −30.4) −26.5) HAQ-DI −0.2 (−0.4, −0.3 (−0.4, −0.5**,^(†) (−0.6,−0.5* (−0.6, −0.5**,^(†) (−0.7, −0.1) −0.1) −0.3) −0.3) −0.4) HAQ-DI ≤MCID, ^(§) 24 (44), 27 (50), 30 (58), 35 (64), 34 (63), n (%), 95% CI31-57 37-63 44-71^(†) 51-76 50-76^(†) hsCRP, mg/L −0.4 (−4.6, −7.9*(−12.2, −9.7** (−14.1, −6.8* (−11.1, −6.9* (−11.1, 3.9) −3.6) −5.4)−2.6) −2.6) Data are mean (95% CI), unless otherwise noted.Abbreviations: ACR—American College of Rheumatology; BID—twice daily;HAQ-DI—Health Assessment Questionnaire-Disability Index;hsCRP—high-sensitivity C-reactive protein; LOCF—last observation carriedforward; MCID—minimal clinically important difference; PhGA—physician'sglobal assessment of disease activity; PtGA—patient global assessment ofdisease activity; RA—rheumatoid arthritis; SJC66—swollen joint countusing 66 joints; TJC68—tender joint count using 68 joints. *P < 0.05;**P < 0.01; ***P < 0.001 relative to placebo. ^(†)1 patient with missingdata. ^(‡)2 patients with missing data. ^(§) MCID = −0.22. Modifiedintent-to-treat population (LOCF).

Safety

The percentage of subjects with any treatment-emergent AEs wasnumerically higher in a dose-dependent manner for the Compound 1 6, 12and 18 mg BID treatment groups compared with placebo (Table 55-C). Mostreported AEs were considered mild to moderate in severity. The mostcommonly observed AEs were headache, nausea, upper respiratory tractinfection, and urinary tract infection. The incidences of serious AEsand severe AEs were low, without an apparent dose-response relationship(Table 55-C). Five subjects in the Compound 1 dose groups reported sevenserious AEs (3 mg BID; one subject each with pancreatitis and pulmonaryembolism, 6 mg BID; one subject with pulmonary embolism and deep veinthrombosis, one patient with TIA and benign prostate hyperplasia, 18 mgBID dose; one subject acute respiratory failure). One subject on placeboexperienced a serious AE of bronchiectasis. The overall infection rateswere similar for the Compound 1 3- and 6 mg BID dose groups and placebo(20%, 22%, and 23%, respectively), but were higher in the Compound 1 12-and 18 mg BID dose groups (40% and 38%). No serious infections werereported in any of the Compound 1 treatment groups. Herpes zosteroccurred in two subjects in the placebo group (4%) and three subjectswho received Compound 1 (1%, one case each in the 3-, 12- and 18 mg BIDgroups; all were isolated to a single dermatome). The two reportedevents of hepatic disorders in the 18 mg BID dose group and one event inthe placebo group were attributed to increased transaminases; none wereserious. There was an adjudicated case of transient ischemic attack(left ventricular hypertrophy, classified as mild) in one subject in theCompound 1 6 mg BID group. One patient in the 6 mg BID group had oneevent each of basal cell carcinoma and squamous cell carcinoma. Therewere no opportunistic infections or deaths during the study period.

Dose-dependent increases in low-density lipoprotein cholesterol (LDL-C)and high-density lipoprotein cholesterol (HDL-C) were observed; however,the ratios of LDL-C/HDL-C remained the same through Week 12. Of thesubjects with normal AST or ALT at baseline, 6-18% of patients onCompound 1 had elevated AST at least twice, and 4-11% had elevated ALTat least twice, versus 2% and 6% on placebo, respectively. The number ofthese subjects was higher in the higher dose groups. Most of theelevations were Grade 1 (for AST and ALT, ≥1.2-<1.6×ULN) and Grade 2(1.6-3.0×ULN). One subject each (2%) in the Compound 1 3 mg BID andplacebo group (2%) had a Grade 3 ALT elevation (3.0-8.0×ULN). Of thesubjects with normal creatinine at baseline, 4-14% subjects on Compound1 had elevated creatinine at least twice versus none in the placebogroup. One subject in the 18 mg BID group had a Grade 3 elevation(≥1.9-≤3.0×ULN). The elevations did not result in discontinuation of anysubject from the study.

Decreases from baseline in mean hemoglobin levels were observed in adose-dependent manner with Compound 1, although mean hemoglobin levelsremained within the normal range across all dose groups during the study(FIG. 38A). Twenty-six out of 219 subjects (11.9%) in the Compound 1groups had a Grade 2 decrease in hemoglobin (from 15-20 g/L); 14/219subjects (6.4%) had a Grade 3 decrease (from 21-29 g/L); 8/219 subjects(3.7%) had a Grade 4 decrease (≥30 g/L). The majority (79%) of thesedecreases were transient (only one occurrence) and one subjectdiscontinued the study due to reported AE of low hemoglobin. However, insubjects with underlying systemic inflammation, as measured by elevatedbaseline hsCRP, treatment with Compound 1 at 3- or 6 mg BID resulted inmean increases from baseline in hemoglobin levels compared with placebo(FIG. 38B). Decreases in mean circulating leukocytes, neutrophils (Table55-D) and natural killer (NK) cells were also observed, and one subjectdiscontinued study drug due to leukopenia. Only NK cell reductionsappeared to be dose-related. The mean percentage change in NK cells was+16.5±46.6 in the placebo group; a dose-dependent decrease was seen insubjects treated with Compound 1 (−15.8±25.3 in the 3 mg BID group,−18.3±47.4 in the 6 mg BID group, −28.0±37.3 in the 12 mg BID group, and−42.6±31.7 in the 18 mg BID group). At all doses of Compound 1, therewas a transient mean increase in total lymphocytes, which returned tobaseline level by Week 12, except in the 18 mg dose group. There weretwo subjects in the 18 mg dose group with Grade 4 lymphocyte reduction;one subject was reported to have vaginal and urinary tract infection,and the other herpes zoster. One subject had a Grade 4 neutrophilreduction, which was not associated with a serious infection.

TABLE 55-C Adverse Events Summary 3 mg 6 mg 12 mg 18 mg Placebo BID BIDBID BID AE, n (%) (n = 56) (n = 55) (n = 55) (n = 55) (n = 55) Any AE 25(45) 26 (47) 31 (56) 37 (67) 39 (71) Any serious AE 1 (2) 2 (4) 2 (4) 01 (2) Any severe AE 2 (4) 1 (2) 2 (4) 2 (4) 1 (2) Any AE leading to 2(4) 0 6 (11) 2 (4) 3 (5) discontinuation Any death 0 0 0 0 0 AEs ofspecial interest Infection 13 (23) 11 (20) 12 (22) 22 (40) 21 (38)Serious infection 1 (2) 0 0 0 0 Cardiovascular 0 0 1 (2)^(†) 0 0 eventHerpes zoster 2 (4) 1 (2) 0 1 (2) 1 (2) Hepatic disorder* 1 (2) 0 0 0 2(4) Malignancy 0 0 1 (2)^(‡) 0 0 Abbreviations: AE—adverse event;BID—twice daily. *AEs as reported by the investigator. ^(†)Thecardiovascular event was adjudicated as a transient ischemic attack.^(‡)One patient with basal cell and squamous cell carcinoma. Safetypopulation

TABLE 55-D Mean Change Over Time in Select Hematology Parameters andIncidence of Patients With Abnormalities Compound 1 3 mg 6 mg 12 mg 18mg Abnormality, Placebo BID BID BID BID number (%) (n = 56)* (n = 55)*(n = 55)* (n = 55) (n = 55) Neutrophils × 10⁹/L Grade 2 1 (2) 0 3 (6) 4(7) 7 (13) (1.0-1.4) Grade 3 0 0 0 2 (4) 1 (2) (0.5-0.9) Grade 4 0 0 0 1(2) 0 (<0.5) Lymphocytes × 10⁹/L Grade 2 18 (33) 14 (26) 19 (35) 14 (25)26 (47) (1.0-1.4) Grade 3 9 (16) 8 (15) 8 (15) 11 (20) 9 (16) (0.5-0.9)Grade 4 0 1 (2) 1 (2) 0 2 (4) (<0.5) BID—twice daily. *1 subject withmissing data. Safety population. Grading based on OMERACT RheumatologyCommon Toxicity Criteria v.2.0

Discussion

In this study, a broad dose range of Compound 1 (dosed up to 18 mg BID)was tested to assess efficacy and safety in subjects with an inadequateresponse or intolerance to anti-TNF biologic therapies. At all doses,Compound 1 demonstrated rapid and robust efficacy as shown bysignificantly greater improvements in clinical and functional outcomescompared to placebo. The onset of improvement with Compound 1 treatmentwas rapid with up to 58% of subjects achieving an ACR20 response asearly as 2 weeks after treatment. The proportion of ACR20 respondersreached a maximum at 8 weeks and plateaued at 71% through Week 12.Improvements in ACR50 (up to 42%) and ACR70 (up to 25%) response ratesin the Compound 1 groups also reached a maximum before Week 12. Thespeed of the response is in contrast to the 3-6 months observed for manybiologic therapies (Bathon, et al., The New England Journal of Medicine,2000, Vol. 343(22), pp. 1586-93; Keystone, et al., Arthritis andRheumatism, 2008, Vol. 58(11), pp. 3319-29; Keystone, et al., Arthritisand Rheumatism, 2004, Vol. 50(5), pp. 1400-11) and comparable with thatobserved for other JAK inhibitors, baricitinib and tofacitinib in TNF-IRpatients. (Burmester, et al., Lancet (London, England), 2013, Vol.381(9865), pp. 451-60; Genovese, et al., European League AgainstRheumatism, 2015; 2015). In addition, the ACR20 response rate wascomparable between subjects with two or more prior anti TNF therapiesand those with only one prior anti-TNF. In general, the maximum efficacywas observed at the 12 mg BID dose.

Despite producing significant clinical improvement in different spectraof RA patients, there are safety concerns with JAK inhibitors,predominantly around impairing the body's ability to fight infections,viral reactivation, as well as altering hematopoietic homeostasis thatcould link to anemia. The most commonly reported adverse events with JAKinhibitors are infections, herpes zoster, pulmonary tuberculosis,cryptococcal pneumonia and pneumocystis pneumonitis (Fleischmann, etal., Arthritis Rheumatol., 2015, Vol. 67(2), pp. 334-43; Genovese, etal., Arthritis Rheumatol., 2016, Vol. 68(1), pp. 46-55). In addition,increases in total cholesterol, elevation of transaminase and serumcreatinine, decreases in neutrophil counts and anemia are also observed.(Burmester, et al., Lancet (London, England), 2013, Vol. 381(9865), pp.451-60; Genovese, et al., Arthritis Rheumatol., 2016, Vol. 68(1), pp.46-55; Keystone, et al., Annals of the Rheumatic Diseases, 2015, Vol. I74(2), pp. 333-40).

In the current study, a broad range of doses of Compound 1 were testedto assess the selectivity of Compound 1 in vivo. Overall, Compound 1demonstrated an acceptable safety and tolerability profile at all dosesin this refractory RA population. There was no serious infection,although the proportion of overall infection rates was higher at the twohighest doses of Compound 1 (12 mg and 18 mg BID). The most commonlyobserved infections with Compound 1 were bronchitis, upper respiratory,and urinary tract infections. The incidence of herpes zoster was similarin the placebo group (two subjects, 4%) and the Compound 1 treatmentgroups (three subjects, 1%), and all were non-disseminated.

At the 12 mg BID and 18 mg BID doses, there was a modest decrease inmean hemoglobin levels by Week 12, although the mean hemoglobin levelsremained within the normal range. Notably, in subjects with elevatedhsCRP at baseline, who were receiving 3 or 6 mg BID Compound 1, meanhemoglobin levels increased compared to placebo treatment, possibly dueto a reduction of systemic inflammation while minimizing inhibitoryeffects on JAK2.

Circulating NK cells, which function as the critical mediator of hostimmunity against malignancy and infections, were measured as apharmacodynamic readout of IL-15 inhibition. With increasing doses ofCompound 1 there was a greater decrease in mean circulating NK cellcounts. At the maximally efficacious dose, 12 mg BID, NK cells decreasedby 28% from baseline, with proportionally smaller decreases in NK cellsobserved at lower doses. Given the fact that IL-15 signaling involves aheterodimer of JAK1 and JAK3, this was to be expected at higher doses ofCompound 1. It is unclear how much each of the heterodimeric components(JAK1 and JAK3) contributes to the overall IL-15 signaling. However, itis possible that at higher exposure of Compound 1, the threshold forin-vivo selectivity for JAK1 compared to JAK3 is lowered in the contextof the JAK1/JAK3 heterodimer. Of note, for tofacitinib at 5 mg BID, thereported median decrease in NK cells at week 24 was ˜35%, with greaterreduction at 10 mg BID or higher doses of tofacitinib (van Vollenhoven,et al., Annals of the Rheumatic Diseases, 2015, pp. 258-9; Addendum toPrimary Clinical Review, NDA 203,214, Center for Drug Evaluation andResearch). However, it is important to note that the significance of NKcell reduction, especially what is considered clinically meaningfulreduction in NK cells in terms of predicting clinical events (i.e. onsetof viral reactivation) is lacking. A significant association with thechanges in nadir NK cells and treated infection rates with tofacitinibtreatment was observed (van Vollenhoven, et al., Annals of the RheumaticDiseases, 2015, pp. 258-9). No association of the reduced NK cells withclinical events was observed in the current study.

As reported with other JAK inhibitors, a dose-dependent elevation of lowdensity lipoprotein cholesterol and high density lipoprotein cholesterollevels was observed with Compound 1, however, the ratio of LDL-C/HDL-Cremained unchanged. For the other laboratory parameters of interest,i.e, serum transaminases, WBC, neutrophil, or lymphocytes, the meanchanges were unremarkable and lacked apparent dose relationship, withonly one subject discontinuing the study early due to leukopenia.

In summary, the results of the current study demonstrated safety andefficacy of a selective JAK1 inhibitor, Compound 1, in adifficult-to-treat population of RA patients who had an inadequateresponse or intolerance to anti-TNF biologic therapies.

Example 56: Treatment of Moderately to Severely Active RheumatoidArthritis in Patients Who have Inadequately Responded to Methotrexate

The following example briefly describes the results of a Phase 2b,12-week, randomized, double-blind, parallel-group, placebo-controlledstudy in which adult subjects with moderately to severely activerheumatoid arthritis (RA) who have inadequately responded to stablemethotrexate therapy were treated with Compound 1.

Patients

Men and women aged≥18 years with active RA and inadequate response tomethotrexate were included in the study. Diagnosis of RA was based onthe 1987 revised American College of Rheumatology (ACR) classificationcriteria (Arnett et al, Arthritis Rheum., 1988, Vol. 31(3), pp. 315-324)or the 2010 ACR/European League Against Rheumatism (EULAR) criteria(Smolen et al, Ann. Rheum. Dis., 2010, Vol. 69(6), pp. 964-975). ActiveRA was defined by minimum disease activity criteria of ≥6 swollen joints(based on 66 joint counts) at screening and baseline; ≥6 tender joints(based on 68 joint counts) at screening and baseline; andhigh-sensitivity C-reactive protein (hsCRP) greater than the upper limitof normal (ULN) or positive test results for both rheumatoid factor andanti-cyclic citrullinated peptide (CCP) at screening. Eligible patientshad been receiving methotrexate for ≥3 months, with a stableprescription (7.5-25 mg/week) for ≥4 weeks before baseline. Stable dosesof methotrexate were continued throughout the study. In addition, allpatients were requested to take a dietary supplement of oral folic acid(or equivalent) from 4 weeks prior to baseline and throughout studyparticipation. All other oral disease-modifying antirheumatic drugs(DMARDs) were discontinued before baseline for ≥5 times the meanterminal elimination half-life of the specific DMARD to ensure washout.High-potency opiates (e.g., oxycodone, methadone, morphine) werediscontinued ≥4 weeks before baseline. All patients had a negativetuberculosis screening assessment or, if there was evidence of a latenttuberculosis infection, completed ≥2 weeks of tuberculosis prophylaxisor had documented completion of a full course of tuberculosisprophylaxis before baseline. Patients were allowed to receivenonsteroidal anti-inflammatory drugs, acetaminophen, oral/inhaledcorticosteroids, and low-potency opiates. Patients were excluded if theyhad received JAK inhibitor therapy or any other investigational orapproved biologic RA therapy.

Treatment

Patients were randomized in a 1:1:1:1:1:1 ratio in a double-blind mannerto oral doses of Compound 1 (immediate release capsules comprisingTartrate Hydrate) 3 mg BID, 6 mg BID, 12 mg BID, 18 mg BID, or 24 mg QD(two 12 mg tablets administered at the same time), or placebo BID for 12weeks. Patients were randomized using an interactive voice/web responsesystem according to a blocked randomization schedule. Investigators,patients, and other study personnel were blinded to the treatmentassignments throughout the study. To maintain blinding, the placebo andactive treatments had an identical appearance. Patients were instructedto take their doses (6 capsules total, split into 2 batches of 3) atapproximately the same times each day.

Assessments

The primary efficacy endpoint was a ≥20% improvement in ACR criteria(ACR20) at week 12. Other endpoints included ACR50 and ACR70 responserates; change in 28-joint Disease Activity Score using C-reactiveprotein (DAS28(CRP)); change in Clinical Disease Activity Index (CDAI);the proportion of patients achieving low disease activity (LDA) orclinical remission based on DAS28(CRP) and CDAI criteria; and change inthe Health Assessment Questionnaire Disability Index (HAQ-DI). Theminimal clinically important difference (MCID) on the HAQ-DI, which is adecrease of ≥0.22, (Strand et al, 2006) was also evaluated.

Safety was evaluated during treatment and for 30 days after the lastdose of study drug on the basis of adverse events (AEs), vital signs,physical examinations, and laboratory tests. AEs were coded using theMedical Dictionary for Regulatory Activities (MeDRA), version 17.1.

Statistical Analyses

The per-protocol primary efficacy analysis was conducted in a modifiedintent-to-treat population, including all randomized patients who takeat least 1 dose of study drug, with last observation carried forward(LOCF) imputation; data were also analyzed with nonresponder imputation(NRI). Statistical tests were 1-sided with a significance level of 0.05for efficacy analyses and 2-sided with a significance level of 0.05 forall other analyses. A sample of 270 patients (45 per randomizedtreatment group) was targeted give 80% power to establish a realdifference of 30% in the primary efficacy endpoint (ACR20 response rateat week 12), assuming the response rate would be 30% in the placebogroup and 60% in at least 1 of the Compound 1 dose groups.

Results

Patients

A total of 300 patients were randomized, and 299 received placebo (n=50)or Compound 1 3 mg BID (n=50), 6 mg BID (n=50), 12 mg BID (n=50), 18 mgBID (n=50), or 24 mg QD (n=49). Overall, 91% of patients completed thestudy, with similar discontinuation rates across treatment groups and noapparent relationship between Compound 1 dose and discontinuation (FIGS.40A and 40B). Demographic and clinical characteristics at baseline werebalanced among treatment groups (Table 56-A). Patients were from EasternEurope (61%), Central/South America (18%), the United States (10%),Western Europe (8%), or other regions (4%). Patients had a mean diseaseduration of 6.9 years and 17.7% had used ≥1 prior non-methotrexateDMARD. Of note, patients with normal hsCRP could be enrolled if theywere positive for rheumatoid factor and anti-CCP antibody. Approximately43% of patients had hsCRP values≤ULN at baseline.

TABLE 56-A Baseline Characteristics and Disease Activity in PatientsWith Inadequate Response to Methotrexate Compound 1 Placebo 3 mg BID 6mg BID 12 mg BID 18 mg BID 24 mg QD Characteristic (n = 50) (n = 50) (n= 50) (n = 50) (n = 50) (n = 49) Female, number (%) 38 (76) 40 (80) 34(68) 41 (82) 42 (84) 42 (86) Age, years, mean (SD) 55 (12) 53 (12) 55(12) 56 (12) 55 (14) 56 (12) Years since RA 5.9 (5.3) 3.9 (3.8) 7.0(5.5) 9.3 (8.6) 7.3 (7.9) 8.3 (7.1) diagnosis, mean (SD) RF positive,number 41 (82) 45 (90) 46 (92) 44 (88) 41 (82) 44 (90) (%) Anti-CCPpositive, 39 (78) 40 (80) 45 (90) 43 (86) 40 (80) 45 (92) number (%)Methotrexate dose, 16 (4) 16 (4) 16 (4) 14 (4) 15 (5) 15 (4) mg, mean(SD) Prednisolone dose, 0 0 0 0 mg, mean (SD) ≥1 prior non-MTX 7 (14) 6(12) 12 (24) 11 (22) 5 (10) 12 (24) DMARD, number (%)  1 6 (12) 4 (8) 10(20) 9 (18) 2 (4) 8 (16)  2 1 (2) 2 (4) 1 (2) 1 (2) 1 (2) 3 (6) ≥3 0 0 1(2) 1 (2) 2 (4) 1 (2) Disease Activity TJC68, mean (SD) 29 (16) 27 (15)28 (16) 28 (13) 27 (15) 28 (16) SJC66, mean (SD) 19 (12) 15 (8) 19 (12)17 (11) 17 (12) 18 (13) HAQ-DI, mean (SD) 1.4 (0.7) 1.3 (0.7) 1.6 (0.7)1.5 (0.6) 1.6 (0.6) 1.5 (0.7) DAS28(CRP), mean 5.6 (1.1) 5.5 (1.1) 5.8(1.0) 5.6 (0.9) 5.7 (0.8) 5.7 (1.0) (SD) CDAI, mean (SD) 40 (14) 38 (13)43 (14) 39 (12) 40 (13) 41 (13) hsCRP, mg/L, mean 15 (26) 11 (15) 17(20) 11 (15) 13 (15) 14 (16) (SD) hsCRP > ULN, * 27 (54) 25 (50) 31 (62)26 (52) 28 (56) 33 (67) number (%)

Efficacy

The primary per-protocol endpoint, ACR20 at week 12 (LOCF imputation),was met at every dose of Compound 1 except the lowest dose of 3 mg BID.The proportions of patients with ACR20 were 65% (P=0.153), 73% (P=0.18),82% (P=0.001), 77% (P=0.008), and 82% (P=0.001) at 3 mg BID, 6 mg BID,12 mg BID, 18 mg BID, and 24 mg QD, respectively, versus the placeboresponse rate (50%). ACR20 responses (NRI) were significantly higherwith Compound 1 at 6 mg BID (68%), 12 mg BID (80%), and 24 mg QD (76%)versus placebo (46%; FIG. 41). Responses with more stringent criteria,i.e., ACR50 and ACR70, were achieved at week 12 by significantly higherpercentages of patients who received Compound 1 versus placebo at alldoses except 12 mg BID for ACR70 response (NRI; FIG. 41). ACR20 responserates increased over time with Compound 1 to reach mean maximum valuesat weeks 6 to 12 (FIG. 42A). ACR50 responses were significant from week4 onward and plateaued at week 8 (FIG. 42B); ACR70 responses alsoappeared to plateau by week 8, with some further improvements up to week12 (FIG. 42C). At the first assessment (week 2), ACR20 responses withCompound 1 ranged from 30% to 44% and were significantly higher at alldoses in patients who received Compound 1 versus placebo (12%). Meandecreases in DAS28(CRP) improved over time from baseline, ranging from−2.2 to −2.6 with Compound 1 at week 12, and were significantly lowercompared with placebo (−1.3) at all Compound 1 doses and every timepoint (FIG. 42D).

Higher percentages of patients who received Compound 1 achievedDAS28(CRP)≤3.2 or <2.6 compared with placebo. The DAS28(CRP)≤3.2 cutoffwas achieved by a significantly higher percentage of patients (41%-52%)at all doses of Compound 1 compared with placebo (20%); the <2.6 cutoffwas achieved by significantly higher proportions (34%-40%) with Compound1 compared with placebo (14%) at all doses except 24 mg QD (22%; FIG.43A). Similarly, CDAI≤10 was achieved by a significantly higherpercentage of patients (40%-46%) compared with placebo (20%) withCompound 1 at all doses except 24 mg QD (35%; FIG. 43B).

Improvements from baseline in ACR component scores were larger withCompound 1 compared with placebo, reaching statistical significance formost comparisons at doses of 6 mg BID and greater (Table 56-B). Changesfrom baseline on the HAQ-DI at week 12 with Compound 1 ranged from −0.6to −0.8 and were significantly greater than that seen with placebo(−0.4) for all but the Compound 1 24 mg QD dose (−0.6). Numerically,more patients in the Compound 1 dose groups≥6 mg BID (69%-88%) met theMCID at week 12 compared with placebo (67%); the study was not poweredfor this analysis, and the comparisons versus placebo mostly were notstatistically significant.

TABLE 56-B Mean Changes From Baseline in ACR Components at Week 12Compound 1 Placebo 3 mg BID 6 mg BID 12 mg BID 18 mg BID 24 mg QD ACRComponent (n = 50) (n = 50) (n = 50) (n = 50) (n = 50) (n = 49) TJC68−14.4 −15.9 −19.2* −19.2* −17.4 −18.9* SJC66 −9.9 −12.1 −11.9 −12.7*−13.2* −13.1* Patient's assessment −19.9 −25.3 −33.8** −33.4** −34.9**−29.8* of pain Physician's global −28.0 −34.7 −43.0*** −45.6*** −36.6*−37.6* assessment of disease activity Patient's global −17.5 −26.9−31.4** −23.8 −29.1* −24.1 assessment of disease activity HAQ-DI −0.4−0.6* −0.7** −0.8*** −0.6* −0.6 HAQ-DI ≤ MCID,^(§) 30 (67), 33 (67), 34(69), 44 (88), 35 (74), 38 (78), number (%), 95% CI 53-80 54-81 57-8279-97 62-87 66-89 hsCRP −0.4 −10.5*** −8.8*** −8.9*** −7.5** −8.4***Abbreviations: ACR—American College of Rheumatology; BID—twice daily;HAQ-DI—Health Assessment Questionnaire Disability Index;hsCRP—high-sensitivity C-reactive protein; LOCF—last observation carriedforward; MCID—minimal clinically important difference; QD—once daily;RA—rheumatoid arthritis; SJC66—swollen joint count using 66 joints;TJC68—tender joint count using 68 joints. *P < 0.05; **P < 0.01; ***P <0.001 relative to placebo. ^(§)MCID = −0.22. Modified intent-to-treatpopulation with LOCF imputation of missing values. 95% CIs werecalculated based on a normal approximation to the binomial distribution.

As can be seen from these results, Compound 1 had an early onset ofaction in subjects who have demonstrated a prior inadequate response tomethotrexate. In particular, ACR20 response rates improved starting atweek 2, with a maximum effect achieved as early as week 6, withcontinued improvement in some dose groups through week 12. ACR50(maximum efficacy up to 50%) and ACR70 (maximum efficacy up to 28%)response rates also quickly plateaued by about week 8. Compound 1 showeda dose-dependent efficacy that seemed to reach a maximum at 12 mg BID.

Safety

The safety and tolerability profile of Compound 1 across doses wasacceptable (Table 56-C). Incidence of any AE was statisticallysignificantly higher with Compound 1 overall versus placebo (45% vs 26%;P=0.012), with a trend of dose dependence. Among common AEs, those thatoccurred in ≥3% patients in any group were abdominal pain, abdominalpain upper, back pain, blood creatine phosphokinase increased, cough,diarrhea, dyslipidemia, dyspepsia, gastroenteritis, headache, herpeszoster, influenza, leukopenia, nasopharyngitis, upper respiratory tractinfection, urinary tract infection, white blood cell count decreased,and wound. Most AEs in the Compound 1 treatment groups were mild ormoderate in severity. Severe AEs occurred in 1 patient each withCompound 1 at 6 mg BID (lung cancer at posttreatment day 10 in a79-year-old male patient with family and smoking histories; the patientdied 3 months later), 12 mg BID (pyrexia), 18 mg BID(hyperbilirubinemia), and 24 mg QD (head injury). There were 2 seriousAEs with Compound 1 that were considered possibly related to study drug:community-acquired pneumonia at 12 mg BID and syncope at 24 mg QD.Infections overall occurred in 20% of patients who received Compound 1and 14% who received placebo, with no tendency towards higher rates athigher doses. Three herpes zoster infections, 1 with Compound 1 at 3 mgBID and 2 at 24 mg QD, involved 1 dermatome per patient. A patient inthe Compound 1 6 mg BID group, aged 79 years and with a history ofsmoking, was diagnosed with lung cancer 10 days after stopping studytreatment and died 3 months later.

At week 12, mean values for alanine aminotransferase (ALT) weresignificantly higher with Compound 1 18 mg BID than with placebo; meanvalues for aspartate aminotransferase (AST) were significantly higherthan placebo with all Compound 1 doses >3 mg BID (Table 56-D). However,grade 3/4 ALT or AST abnormalities during the study were sporadic, withno clear dose dependence (Table 56-E). Creatinine and creatinephosphokinase levels were significantly higher in all Compound 1 dosegroups compared with placebo. Compound 1 was associated with elevationsin high-density and low-density lipoprotein cholesterol (HDL-C; LDL-C);HDL-C elevation was statistically significant at 6 mg BID, whereas LDL-Cvalues were significantly higher than placebo for all Compound 1 doses;however, the ratios of LDL-C/HDL-C remained the same through week 12.There were no significant decreases in lymphocyte or neutrophil levelsbetween placebo and Compound 1 dose groups by week 12. Grade 3lymphocyte values occurred with placebo and all doses of Compound 1;grade 4 values occurred in 1 patient each with Compound 1 at 3 mg BIDand 18 mg BID (Table 56-E). Grade 3 neutrophil values occurred withCompound 1 at 12 mg BID (1 patient), 18 mg BID (3 patients), and 24 mgQD (1 patient). Natural killer (NK) cell percentages were significantlylower than placebo with Compound 1 doses≥6 mg BID (Table 56-D).

Mean changes in hemoglobin over time in all patients, patients withhsCRP values≤5 mg/mL, and patients with hsCRP values >5 mg/mL are shownin FIGS. 44A-44C. Mean hemoglobin values remained stable or increased atlower doses, most notably in patients with elevated CRP at baseline.Dose-dependent decreases in hemoglobin were seen at higher doses withoutclinical impact.

TABLE 56-C Adverse Events Summary Compound 1 Placebo 3 mg BID 6 mg BID12 mg BID 18 mg BID 24 mg QD AE, number (%) (n = 50) (n = 50) (n = 50)(n = 50) (n = 50) (n = 49) Overall AEs Any AE 13 (26) 19 (38) 23 (46) 29(58) 25 (50) 17 (35) Any AE possibly  6 (12)  5 (10)  6 (12) 17 (34) 11(22)  5 (10) drug related* Any serious AE 0 0 2 (4) 1 (2) 3 (6) 2 (4)Any serious AE 0 0 0 1 (2) 0 1 (2) possibly drug related* Any severe AE0 0 1 (2) 1 (2) 1 (2) 1 (2) Any AE leading to 1 (2) 1 (2) 1 (2) 1 (2)  5(10) 1 (2) discontinuation Any AE leading to 0 0 0 0 0 0 death AEs ≥3%in any group Abdominal pain 0 1 (2) 1 (2) 2 (4) 0 1 (2) Abdominal pain 00 0 2 (4) 1 (2) 1 (2) upper Back pain 0 1 (2) 3 (6) 1 (2) 0 1 (2) Bloodcreatine 0 0 0 3 (6) 2 (4) 1 (2) phosphokinase increased Cough 0 1 (2) 1(2) 3 (6) 1 (2) 0 Diarrhea 0 0 1 (2) 3 (6) 1 (2) 1 (2) Dyslipidemia 0 1(2) 0 3 (6) 0 0 Dyspepsia 1 (2) 0 0 0 2 (4) 0 Gastroenteritis 0 2 (4) 00 0 1 (2) Headache 1 (2) 2 (4) 1 (2) 3 (6) 0 1 (2) Herpes zoster 0 1 (2)0 0 0 2 (4) Influenza 0 0 0 4 (8) 1 (2) 0 Leukopenia 0 0 0 3 (6) 1 (2) 0Nasopharyngitis 1 (2) 1 (2) 2 (4) 4 (8) 2 (4) 3 (6) Upper respiratory 00 1 (2) 1 (2) 2 (4) 0 tract infection Urinary tract 2 (4) 2 (4) 2 (4) 2(4) 0 2 (4) infection White blood cell 0 0 1 (2) 0 2 (4) 0 countdecreased Wound 0 0 2 (4) 0 0 0 AEs of special interest Infection  7(14) 10 (20)  7 (14) 12 (24) 11 (22)  9 (18) Serious infection 0 0 0 1(2) 0 0 Cardiovascular 0 0 0 0 0  1 (2)* event Herpes zoster^(†) 0 1 (2)0 0 0 2 (4) Hepatic disorder 0 0 0 0 2 (4) 0 Malignancy 0 0  1 (2)^(‡) 00 0 Abbreviations: AE—adverse event; BID—twice daily; QD—once daily.*The cardiovascular event was a cerebrovascular accident and wasadjudicated as an ischemic stroke. ^(†)The events of herpes zosterinvolved 1 dermatome per patient. ^(‡)Lung cancer at posttreatment day10 in a 79-year-old male patient with family and smoking histories. Thepatient died 3 months later. Safety analysis population.

TABLE 56-D Mean Changes in Laboratory Values of Interest at Week 12Compound 1 Mean (SD) Placebo 3 mg BID 6 mg BID 12 mg BID 18 mg BID 24 mgQD Value (n = 50) (n = 50) (n = 50) (n = 50) (n = 50) (n = 49) ALT, U/L−1.3 (15.4) −1.1 (20.7) 6.5 (10.0) 7.0 (31.8) 8.5 (18.5)* 5.3 (20.7)AST, U/L −0.1 (8.4) 1.9 (11.9) 6.6 (5.5)** 7.6 (14.3)** 7.7 (11.3)** 4.8(10.9)* HDL-C, 0.01 (0.21) 0.12 (0.32) 0.17 (0.26)* 0.13 (0.30) 0.13(0.43) 0.13 (0.33) mmol/L LDL-C, −0.05 (0.43) 0.28 (0.82)* 0.34 (0.71)*0.49 (0.93)** 0.27 (0.83)* 0.32 (0.62)** mmol/L Creatinine, −0.9 (7.9)2.0 (8.2)** 4.9 (9.1)** 4.3 (7.1)** 4.6 (10.2)** 5.4 (8.5)** μmol/LCreatine −7.7 (90.1) 40.2 (46.5)* 82.5 (80.6)** 100.4 (126.5)** 108.7(140.2)** 59.4 (94.0)** phosphokinase, U/L Lymphocytes, × −0.09 (0.50)0.12 (0.58) 0.01 (0.79) −0.08 (0.67) −0.12 (0.53) −0.13 (0.49) 10⁹/LNeutrophils, × −0.5 (2.20) −1.1 (2.13) −0.9 (1.60) −0.9 (1.90) −0.9(2.16) −0.4 (1.99) 10⁹/L NK cells, −0.1 (4.46) −1.3 (4.54) −3.1 (4.09)**−3.3 (4.67)** −5.3 (4.24)** −4.9 (5.12)** CD3−/16−/56+, %_(†)Abbreviations: ALT—alanine aminotransferase; AST—aspartateaminotransferase; BID—twice daily; HDL-C—high-density lipoproteincholesterol; LDL-C—low-density lipoprotein cholesterol; NK—naturalkiller; QD—once daily. *P < 0.05; **P < 0.01 relative to placebo; Pvalue for difference between treatment groups in baseline and meanchange from baseline using a contrast within the one-way analysis ofvariance. ^(†)Mean percentage change from baseline at week 12. Safetyanalysis population.

TABLE 56-E Incidence of Patients With Laboratory Abnormalities at Week12 Compound 1 Placebo 3 mg BID 6 mg BID 12 mg BID 18 mg BID 24 mg QD (n= 50) (n = 50) (n = 50) (n = 50) (n = 50) (n = 49) ALT, U/L Grade 3(3.0-8.0 × 0 0 1 2 1 0 ULN) Grade 4 (>8.0 × 0 0 0 0 1 0 ULN) AST, U/LGrade 3 (3.0-8.0 × 0 1 1 0 1 0 ULN) Grade 4 (>8.0 × 0 0 0 0 0 0 ULN)Neutrophils, × 10⁹/L Grade 3 (0.5-0.9) 0 0 0 1 3 1 Grade 4 (<0.5) 0 0 00 0 0 Lymphocytes, × 10⁹/L Grade 3 (0.5-0.9) 7 8 13 16 17 15 Grade 4(0.5) 0 1 0 0 1 0 Abbreviations: ALT—alanine aminotransferase;AST—aspartate aminotransferase; BID—twice daily; QD—once daily;ULN—upper limit of normal.

As can be seen from these results, the safety and tolerability profileof Compound 1 was acceptable across doses.

All references (patent and non-patent) cited above are incorporated byreference into this patent application. The discussion of thosereferences is intended merely to summarize the assertions made by theirauthors. No admission is made that any reference (or a portion of anyreference) is relevant prior art (or prior art at all). Applicantsreserve the right to challenge the accuracy and pertinence of the citedreferences.

We claim:
 1. Crystalline(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(Compound 1) selected from the group consisting of: a. crystallinefreebase Compound 1 having an X-ray powder diffraction patterncharacterized by peaks at 7.9±0.2, 10.3±0.2, and 13.4±0.2 degrees twotheta when measured at about 25° C. with monochromatic Kai radiation; b.crystalline freebase Compound 1 having an X-ray powder diffractionpattern characterized by peaks at 9.7±0.2, 14.2±0.2, and 20.3±0.2degrees two theta when measured at about 25° C. with monochromatic Kairadiation; and c. crystalline tartrate Compound 1 having an X-ray powderdiffraction pattern characterized by peaks at 3.9±0.2, 14.1±0.2, and15.7±0.2 degrees two theta when measured at about 25° C. withmonochromatic Kα1 radiation.
 2. A solid composition comprising a solidstate form of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(Compound 1), wherein at least about 80% by weight of the solid stateform is an amorphous freebase of Compound
 1. 3. A process for preparinga pharmaceutical composition containing a pharmaceutically acceptablecarrier and an amorphous freebase of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(Compound 1), comprising contacting a crystalline freebase of Compound 1with the pharmaceutically acceptable carrier, wherein crystallinefreebase of Compound 1 is converted into amorphous freebase ofCompound
 1. 4. A pharmaceutical composition comprising apharmaceutically acceptable carrier and an amorphous freebase of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(Compound 1), prepared by the process of claim
 3. 5. The crystallinefreebase Compound 1 of claim 1, having an X-ray powder diffractionpattern characterized by peaks at 7.9±0.2, 10.3±0.2, and 13.4±0.2degrees two theta when measured at about 25° C. with monochromatic Kα1radiation.
 6. The crystalline freebase Compound 1 of claim 5, having anX-ray powder diffraction pattern characterized by peaks at 7.9±0.2,10.3±0.2, and 13.4±0.2 degrees two theta when measured at about 25° C.with monochromatic Kα1 radiation, and further characterized by at leastone additional peak selected from the group consisting of 15.1±0.2,15.5±0.2, 17.0±0.2, 17.2±0.2, 18.3±0.2, 19.3±0.2, 20.5±0.2, 20.9±0.2,21.7±0.2, 21.9±0.2, and 24.9±0.2 degrees two theta when measured atabout 25° C. with monochromatic Kα1 radiation.
 7. The crystallinefreebase Compound 1 of claim 5, which is a hemihydrate.
 8. Thecrystalline freebase Compound 1 of claim 1, having an X-ray powderdiffraction pattern characterized by peaks at 9.7±0.2, 14.2±0.2, and20.3±0.2 degrees two theta when measured at about 25° C. withmonochromatic Kα1 radiation.
 9. The crystalline freebase Compound 1 ofclaim 8, having an X-ray powder diffraction pattern characterized bypeaks at 9.7±0.2, 14.2±0.2, and 20.3±0.2 degrees two theta when measuredat about 25° C. with monochromatic Kα1 radiation, and furthercharacterized by at least one additional peak selected from the groupconsisting of 8.0±0.2, 14.5±0.2, 23.0±0.2, and 24.7±0.2 degrees twotheta when measured at about 25° C. with monochromatic Kα1 radiation.10. The crystalline freebase Compound 1 of claim 8, which is ananhydrate.
 11. The crystalline tartrate Compound 1 of claim 1, having anX-ray powder diffraction pattern characterized by peaks at 3.9±0.2,14.1±0.2, and 15.7±0.2 degrees two theta when measured at about 25° C.with monochromatic Kα1 radiation, wherein the crystalline tartrateCompound 1 is a tetrahydrate.
 12. The crystalline tartrate Compound 1 ofclaim 1, having an X-ray powder diffraction pattern characterized bypeaks at 3.9±0.2, 14.1±0.2, and 15.7±0.2 degrees two theta when measuredat about 25° C. with monochromatic Kα1 radiation, and furthercharacterized by at least one additional peak selected from the groupconsisting of 6.8±0.2, 11.8±0.2, 18.0±0.2, 21.9±0.2, and 25.9±0.2degrees two theta when measured at about 25° C. with monochromatic Kα1radiation.
 13. The crystalline tartrate Compound 1 of claim 12, which isa tetrahydrate.
 14. The composition of claim 2, wherein the amorphousfreebase comprises blade or irregular morphology.
 15. The composition ofclaim 14, wherein the blade morphology comprises hexagonal crystalfaces.
 16. The composition of claim 2, further comprising tartarticacid.
 17. The composition of claim 2, wherein at least about 98% byweight of the solid state form is the amorphous freebase of Compound 1.18. The composition of claim 2, wherein the composition comprises thesolid state form dispersed in a hydrophilic polymer.
 19. The compositionof claim 2, wherein the amorphous freebase of Compound 1 in thecomposition exhibits no growth of degradation products after storage at50° C. and 75% relative humidity in an open or closed glass vial for atleast six weeks.
 20. The process of claim 3, wherein the contactingcomprises dispersing the crystalline freebase of Compound 1 in thepharmaceutically acceptable carrier.
 21. The process of claim 3, whereinthe pharmaceutically acceptable carrier is a hydrophilic polymer. 22.The process of claim 3, wherein at least about 80% by weight ofcrystalline freebase of Compound 1 is converted into amorphous freebaseof Compound
 1. 23. The process of claim 3, wherein at least about 98% byweight of crystalline freebase of Compound 1 is converted into amorphousfreebase of Compound
 1. 24. The process of claim 3, wherein thecrystalline freebase of Compound 1 is selected from the group consistingof: a. crystalline freebase Compound 1 having an X-ray powderdiffraction pattern characterized by peaks at 7.9±0.2, 10.3±0.2, and13.4±0.2 degrees two theta when measured at about 25° C. withmonochromatic Kα1 radiation; b. crystalline freebase Compound 1 havingan X-ray powder diffraction pattern characterized by peaks at 9.7±0.2,14.2±0.2, and 20.3±0.2 degrees two theta when measured at about 25° C.with monochromatic Kα1 radiation; and c. crystalline tartrate Compound 1having an X-ray powder diffraction pattern characterized by peaks at3.9±0.2, 14.1±0.2, and 15.7±0.2 degrees two theta when measured at about25° C. with monochromatic Kα1 radiation.
 25. The pharmaceuticalcomposition of claim 4, comprising a dispersion of the amorphousfreebase of Compound 1 in the pharmaceutically acceptable carrier. 26.The pharmaceutical composition of claim 4, wherein the pharmaceuticallyacceptable carrier is a hydrophilic polymer.
 27. The pharmaceuticalcomposition of claim 4, wherein at least about 80% by weight of theCompound 1 present in the composition is the amorphous freebase ofCompound
 1. 28. The pharmaceutical composition of claim 4, wherein atleast about 98% by weight of the Compound 1 present in the compositionis the amorphous freebase of Compound
 1. 29. The pharmaceuticalcomposition of claim 25, wherein at least about 80% by weight of theCompound 1 present in the composition is the amorphous freebase ofCompound
 1. 30. The pharmaceutical composition of claim 25, wherein atleast about 98% by weight of the Compound 1 present in the compositionis the amorphous freebase of Compound 1.